The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation.
Kelley Nathan,Jeltema Devon,Duan Yanhui,He Yuan
International journal of molecular sciences
The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer's disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.
Sirtuin and metabolic kidney disease.
Wakino Shu,Hasegawa Kazuhiro,Itoh Hiroshi
Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.
High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney.
Yamamoto Takeshi,Takabatake Yoshitsugu,Takahashi Atsushi,Kimura Tomonori,Namba Tomoko,Matsuda Jun,Minami Satoshi,Kaimori Jun-Ya,Matsui Isao,Matsusaka Taiji,Niimura Fumio,Yanagita Motoko,Isaka Yoshitaka
Journal of the American Society of Nephrology : JASN
Excessive fat intake contributes to the progression of metabolic diseases cellular injury and inflammation, a process termed lipotoxicity. Here, we investigated the role of lysosomal dysfunction and impaired autophagic flux in the pathogenesis of lipotoxicity in the kidney. In mice, a high-fat diet (HFD) resulted in an accumulation of phospholipids in enlarged lysosomes within kidney proximal tubular cells (PTCs). In isolated PTCs treated with palmitic acid, autophagic degradation activity progressively stagnated in association with impaired lysosomal acidification and excessive lipid accumulation. Pulse-chase experiments revealed that the accumulated lipids originated from cellular membranes. In mice with induced PTC-specific ablation of autophagy, PTCs of HFD-mice exhibited greater accumulation of ubiquitin-positive protein aggregates normally removed by autophagy than did PTCs of mice fed a normal diet. Furthermore, HFD-mice had no capacity to augment autophagic activity upon another pathologic stress. Autophagy ablation also exaggerated HFD-induced mitochondrial dysfunction and inflammasome activation. Moreover, renal ischemia-reperfusion induced greater injury in HFD-mice than in mice fed a normal diet, and ablation of autophagy further exacerbated this effect. Finally, we detected similarly enhanced phospholipid accumulation in enlarged lysosomes and impaired autophagic flux in the kidneys of obese patients compared with nonobese patients. These findings provide key insights regarding the pathophysiology of lipotoxicity in the kidney and clues to a novel treatment for obesity-related kidney diseases.
Immunometabolic rewiring of tubular epithelial cells in kidney disease.
Nature reviews. Nephrology
Kidney tubular epithelial cells (TECs) have a crucial role in the damage and repair response to acute and chronic injury. To adequately respond to constant changes in the environment, TECs have considerable bioenergetic needs, which are supported by metabolic pathways. Although little is known about TEC metabolism, a number of ground-breaking studies have shown that defective glucose metabolism or fatty acid oxidation in the kidney has a key role in the response to kidney injury. Imbalanced use of these metabolic pathways can predispose TECs to apoptosis and dedifferentiation, and contribute to lipotoxicity and kidney injury. The accumulation of lipids and aberrant metabolic adaptations of TECs during kidney disease can also be driven by receptors of the innate immune system. Similar to their actions in innate immune cells, pattern recognition receptors regulate the metabolic rewiring of TECs, causing cellular dysfunction and lipid accumulation. TECs should therefore be considered a specialized cell type - like cells of the innate immune system - that is subject to regulation by immunometabolism. Targeting energy metabolism in TECs could represent a strategy for metabolically reprogramming the kidney and promoting kidney repair.
Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome.
Prieur Xavier,Roszer Tamás,Ricote Mercedes
Biochimica et biophysica acta
Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFkappaB) and the key roles played by the PPAR and LXR nuclear receptors-lipid sensors that link lipid metabolism and inflammation.
Muscle insulin resistance: assault by lipids, cytokines and local macrophages.
Kewalramani Girish,Bilan Philip J,Klip Amira
Current opinion in clinical nutrition and metabolic care
PURPOSE OF REVIEW:The present review outlines possible mechanisms by which high fatty acids, associated with high-fat diet and obesity, impose insulin resistance on glucose uptake into skeletal muscle. RECENT FINDINGS:It is well established that muscle insulin resistance arises in conditions of high-fatty acid availability, and correlates with accumulation of triglycerides within skeletal muscle fibres. However, it is debated whether triglycerides or other lipid metabolites such as diacylglycerols and ceramides are directly responsible. These lipid metabolites can activate serine kinases that impair insulin signalling. Accumulation of acylcarnitines and reactive oxygen species could be additional causative agents of insulin resistance. Further, the precise defects in insulin signalling in muscle caused by high intramuscular lipid (i.e. lipotoxicity) remain unclear. In parallel, proinflammatory activation within the adipose tissue of obese and high-fat fed animals or humans causes muscle insulin resistance, and is ascribed to circulating inflammatory cytokines. Recent evidence also shows proinflammatory macrophages infiltrating muscle tissue and/or intermuscular adipose tissue, and there is growing evidence that fatty acids trigger macrophages to secrete factors that directly impair insulin actions. These factors are postulated to activate stress-signalling pathways in muscle that act on the same insulin-signalling components affected by lipotoxicity. SUMMARY:Altered intramuscular lipid metabolism, circulating cytokines, and inflammatory macrophage infiltration of muscle tissue have been recently linked to muscle insulin resistance provoked by fatty acids. Each is analysed separately in this review, but they may act simultaneously and synergistically to render skeletal muscle insulin-resistant.
The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes.
Current diabetes reports
The widespread epidemics of obesity and type 2 diabetes mellitus (T2DM) suggest that both conditions are closely linked. An increasing body of evidence has shifted our view of adipose tissue from a passive energy depot to a dynamic "endocrine organ" that tightly regulates nutritional balance by means of a complex crosstalk of adipocytes with their microenvironment. Dysfunctional adipose tissue, particularly as observed in obesity, is characterized by adipocyte hypertrophy, macrophage infiltration, impaired insulin signaling, and insulin resistance. The result is the release of a host of inflammatory adipokines and excessive amounts of free fatty acids that promote ectopic fat deposition and lipotoxicity in muscle, liver, and pancreatic beta cells. This review focuses on recent work on how glucose homeostasis is profoundly altered by distressed adipose tissue. A better understanding of this relationship offers the best chance for early intervention strategies aimed at preventing the burden of T2DM.
Fatty acids, lipid mediators, and T-cell function.
de Jong Anja J,Kloppenburg Margreet,Toes René E M,Ioan-Facsinay Andreea
Frontiers in immunology
Research toward the mechanisms underlying obesity-linked complications has intensified during the last years. As a consequence, it has become clear that metabolism and immunity are intimately linked. Free fatty acids and other lipids acquired in excess by current feeding patterns have been proposed to mediate this link due to their immune modulatory capacity. The functional differences between saturated and unsaturated fatty acids, in combination with their dietary intake are believed to modulate the outcome of immune responses. Moreover, unsaturated fatty acids can be oxidized in a tightly regulated and specific manner to generate either potent pro-inflammatory or pro-resolving lipid mediators. These oxidative derivatives of fatty acids have received detailed attention during the last years, as they have proven to have strong immune modulatory capacity, even in pM ranges. Both fatty acids and oxidized fatty acids have been studied especially in relation to macrophage and T-cells functions. In this review, we propose to focus on the effect of fatty acids and their oxidative derivatives on T-cells, as it is an active area of research during the past 5 years. The effect of fatty acids and their derivatives on activation and proliferation of T-cells, as well as the delicate balance between stimulation and lipotoxicity will be discussed. Moreover, the receptors involved in the interaction between free fatty acids and their derivatives with T-cells will be summarized. Finally, the mechanisms involved in modulation of T-cells by fatty acids will be addressed, including cellular signaling and metabolism of T-cells. The in vitro results will be placed in context of in vivo studies both in humans and mice. In this review, we summarize the latest findings on the immune modulatory function of lipids on T-cells and will point out novel directions for future research.
The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation.
Advances in experimental medicine and biology
Obesity is characterized by a state of chronic, low-grade inflammation. However, excessive fatty acid release may worsen adipose tissue inflammation and contributes to insulin resistance. In this case, several novel and highly active molecules are released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines. Most likely cytokines that are released by inflammatory cells infiltrating obese adipose tissue are such as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2) and IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation. In this process, toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress through hyperactivation of c-Jun N-terminal Kinase (JNK) -Activator Protein 1 (AP1) and inhibitor of nuclear factor kappa-B kinase beta (IKKbeta)-nuclear factor kappa B (NF-kappaB) pathways play an important role, and may also affect vascular endothelial function by modulating vascular nitric oxide and superoxide release. Additionally, systemic oxidative stress, macrophage recruitment, increase in the expression of NOD-like receptor (NLR) family protein (NLRP3) inflammasone and adipocyte death are predominant determinants in the pathogenesis of obesity-associated adipose tissue inflammation. In this chapter potential involvement of these factors that contribute to the adverse effects of obesity are reviewed.
MicroRNA and Adipogenesis.
Engin Ayse Basak
Advances in experimental medicine and biology
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block expression of master regulators of adipogenesis. Additionally, specific miRNAs have been implicated in adipocyte differentiation and mature adipocyte functions. While, each miRNA targets multiple mRNAs, which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. In this respect, development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity and insulin resistance are effectively controlled by miRNAs.
Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases.
Festuccia William T
Molecular nutrition & food research
SCOPE:Evidence gathered in the last decades suggests that lipotoxicity and inflammation are the main factors connecting adipose tissue dysfunction to the development of metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, among others. The mechanistic target of rapamycin (mTOR) is a serine threonine kinase that functions as the catalytic entity of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). These complexes are important components of signaling pathways activated by nutrients, growth factors, and inflammatory mediators and are therefore directly involved in the regulation of adipocyte and macrophage metabolism and function. METHODS AND RESULTS:In this article, studies that evaluate the involvement of mTORC1 and 2 in the regulation of macrophage and adipocyte function and their implication in the development of metabolic-disease-associated adipose tissue dysfunction are reviewed. CONCLUSION:In adipocytes, optimal levels of mTORC1 activity are required for its pro-lipogenic actions, while in macrophages, mTORC1 regulates features of both M1 and M2 polarization. mTORC2, on the other hand, promotes glucose uptake and de novo lipogenesis in adipocytes and counteracts macrophage inflammatory response.
Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation.
Mouton Alan J,Li Xuan,Hall Michael E,Hall John E
Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation has been implicated in macrophage polarization. M1 macrophages primarily rely on glycolysis, whereas M2 macrophages rely on the tricarboxylic acid cycle and oxidative phosphorylation; thus, factors that affect macrophage metabolism may disrupt M1/M2 homeostasis and exacerbate inflammation. The mechanisms by which obesity and hypertension may synergistically induce macrophage metabolic dysfunction, particularly during cardiac remodeling, are not fully understood. We propose that obesity and hypertension induce M1 macrophage polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia. We discuss canonical and novel proinflammatory roles of macrophages during obesity-hypertension-induced cardiac injury, including diastolic dysfunction and impaired calcium handling. Finally, we discuss the current status of potential therapies to target macrophage metabolism during heart failure, including antidiabetic therapies, anti-inflammatory therapies, and novel immunometabolic agents.
Lipid scavenging macrophages and inflammation.
Vogel Andrea,Brunner Julia Stefanie,Hajto Alexander,Sharif Omar,Schabbauer Gernot
Biochimica et biophysica acta. Molecular and cell biology of lipids
Macrophages are professional phagocytes, indispensable for maintenance of tissue homeostasis and integrity. Depending on their resident tissue, macrophages are exposed to highly diverse metabolic environments. Adapted to their niche, they can contribute to local metabolic turnover through metabolite uptake, conversion, storage and release. Disturbances in tissue homeostasis caused by infection, inflammation or damage dramatically alter the local milieu, impacting macrophage activation status and metabolism. In the case of persisting stimuli, defective macrophage responses ensue, which can promote tissue damage and disease. Especially relevant herein are disbalances in lipid rich environments, where macrophages are crucially involved in lipid uptake and turnover, preventing lipotoxicity. Lipid uptake is to a large extent facilitated by macrophage expressed scavenger receptors that are dynamically regulated and important in many metabolic diseases. Here, we review the receptors mediating lipid uptake and summarize recent findings on their role in health and disease. We further highlight the underlying pathways driving macrophage lipid acquisition and their impact on myeloid metabolic remodelling.
Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.
Journal of hepatology
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and emerging as the leading cause of liver cirrhosis, liver transplantation and hepatocellular carcinoma (HCC). NAFLD is a metabolic disease and considered the hepatic manifestation of the metabolic syndrome; however, during the evolution of NAFLD from steatosis to nonalcoholic steatohepatitis (NASH), to more advanced stages of NASH with liver fibrosis, the immune system plays an integral role. Triggers for inflammation are rooted in hepatic (lipid overload, lipotoxicity, oxidative stress) and extrahepatic systems (gut-liver axis, adipose tissue, skeletal muscle), resulting in unique immune-mediated pathomechanisms in NAFLD. In recent years, the implementation of single cell RNA-sequencing (scRNA-seq) and high dimensional multi-omics (proteogenomics, lipidomics) and spatial transcriptomics have tremendously advanced our understanding of the complex heterogeneity of various liver immune cell subsets in health and disease. In NAFLD, several emerging inflammatory mechanisms have been uncovered, including tremendous macrophage heterogeneity, auto-aggressive T cells, the role of unconventional T cells and platelet immune cell interactions potentially yielding novel therapeutics. In this review, we will highlight the recent discoveries related to inflammation in NAFLD, discuss the role of immune cell subsets during the different stages of the disease including disease regression and integrate the multiple systems driving inflammation. We propose a refined concept by which the immune system contributes to all stages of NAFLD and discuss open scientific questions arising from this paradigm shift that need to be unraveled in the coming years, being a basis for reliable diagnosis, prognosis of patients at risk. Finally, we discuss novel therapeutic avenues targeting the multiple triggers of inflammation, including combination therapy via nuclear receptors (FXR agonists, PPAR agonists).
Lipids and the progression of renal disease.
Keane W F,O'Donnell M P,Kasiske B L,Schmitz P G
Journal of the American Society of Nephrology : JASN
The mechanisms involved in progressive renal injury have been the subject of intense investigation during the past decade. Hemodynamic and nonhemodynamic factors have been implicated in progressive renal damage, including abnormalities of lipid metabolism. The idea that abnormal lipid metabolism may be important in the development and progression of renal injury has intrigued investigators for over 100 years. Studies in models of progressive renal insufficiency have demonstrated that abnormalities in lipid metabolism may participate in the development of glomerular and tubular alterations leading to nephron destruction. This concept has been supported by the demonstration that pharmacologic intervention with different classes of lipid-lowering agents is associated with a reduction in the extent and severity of glomerular and tubular injury. The mechanism whereby hyperlipidemia contributes to renal injury are at present unknown. Morphologically, marked expansion of the mesangial matrix, prior to the development of glomerulosclerosis, suggests the possibility that altered production of mesangial matrix proteins may contribute to glomerular injury. Increased numbers of glomerular monocyte-derived macrophages and foam cells in hyperlipidemic rats have been described. The role that these cells may play in the development of proteinuria and glomerular damage has not been clarified. Biochemically, increased renal tissue content of cholesterol esters and reduced concentrations of essential fatty acids have been described. Whether these changes in tissue lipids contribute to renal injury is also unknown. In addition, persistent hyperlipidemia, particularly hypercholesterolemia, may also lead to glomerular hypertension, possibly through alterations in eicosanoid metabolism. Finally, preliminary data have suggested that oxidized lipoproteins may contribute to the hemodynamic and structural changes described in lipid-induced renal injury. The roles of altered platelet function and other lipid-derived inflammatory mediators are yet to be explored. In conclusion, experimental studies have indicated that hyperlipidemia is an important modulator of nephron damage and may contribute to the progression of renal disease. Whether alterations in lipid metabolism participate in progressive renal insufficiency in humans remains to be determined.
Contribution of proteinuria to progressive renal injury: consequences of tubular uptake of fatty acid bearing albumin.
Thomas M E,Schreiner G F
American journal of nephrology
Proteinuria is a marker of a poor prognosis in the glomerulonephritides and progressive renal disease. Recent animal studies have directly implicated proteinuria in inflammatory tubulointerstitial injury. The proximal tubule takes up significant amounts of lipid in the human nephrotic syndrome. We propose that proximal tubular uptake and metabolism of lipids, notably fatty acid bearing albumin, contributes to the chronic tubulointerstitial infiltration and injury associated with heavy proteinuria. Work in our laboratory has shown that a novel nonpolar lipid released by proximal tubules endocytosing fatty acid-bearing albumin is a potent macrophage chemoattractant. We have also studied the metabolic destiny of fatty acids liberated upon proximal tubular catabolism of albumin. Palmitate was preferentially metabolized to phosphatidylcholines, phosphatidylinositols and diglycerides. Oleate and linoleate were metabolized to triglycerides. Palmitate was profoundly inhibitory to OK cell growth, whilst oleate was stimulatory. In nephrosis, faced with an unregulated influx of fatty acids on albumin, the proximal tubule metabolizes them to a variety of lipids, some of which have pathological effects. Thus, the metabolism of albumin-bound fatty acids by the proximal tubule during heavy proteinuria may directly underlie subsequent tubulointerstitial inflammation and altered response to injury.
Progression of renal failure: role of apolipoprotein B-containing lipoproteins.
Attman P O,Samuelsson O,Alaupovic P
Kidney international. Supplement
Plasma lipoproteins (LP) may be identified on the basis of density properties or apolipoprotein (apo) composition. ApoB-containing LP occur in VLDL, IDL and LDL. There are several types of apoB-containing LP characterized by specific composition of minor apolipoproteins (apoC, apoE etc.) and lipid constituents (triglycerides and cholesterol), metabolic properties and relative atherogenicity. The alterations of lipoprotein metabolism in renal disease resulting in elevated levels of apoB-containing LP may be reflected in hyperlipidemia. Whereas nephrotic syndrome and heavy proteinuria are associated with increased formation of cholesterol-rich apoB-containing LP in LDL and VLDL, the characteristic feature in renal failure is the accumulation of intact or partially metabolised triglyceride-rich LP in IDL and VLDL. The potentially atherogenic apoB-containing LP have been linked to the pathogenic processes that result in progressive glomerular and interstitial lesions and ultimate loss of renal function. The mechanisms of injury are not fully understood. Receptor- and non-receptor mediated uptake of LP by mesangial cells may induce or accelerate proliferative and sclerotic processes in the glomerular mesangium that are analogous to atherosclerosis in the arterial wall. Changes in glomerular permeability can result in increased filtration of LP that may be internalized by tubular cells and elicit corresponding lesions in the interstitial tissues. The negative impact of proteinuria on the prognosis of renal disease could be mediated in part through an increased filtration of lipoproteins. Induction of hyperlipidemia accelerates glomerular and interstitial damage in experimental renal failure. This can be attenuated by treatment with hypolipemic agents. In patients, increased concentrations of apoB-containing LP are associated with more rapid progression of renal insufficiency in both primary renal disease and diabetic nephropathy. It is, however, presently not known to what extent treatment of the renal dyslipidemia can modify the progression of chronic renal failure. Experimental and clinical evidence suggest that apoB-containing LP may play a pathogenetic role in the progression of renal disease.
Renal lipotoxicity: Insights from experimental models.
Castro Barbara Bruna Abreu,Foresto-Neto Orestes,Saraiva-Camara Niels Olsen,Sanders-Pinheiro Helady
Clinical and experimental pharmacology & physiology
In recent decades, there has been a progressive increase in the prevalence of obesity and chronic kidney disease. Renal lipotoxicity has been associated with obesity. Although lipids play fundamental physiological roles, the accumulation of lipids in kidney cells may cause dysfunction and/or renal fibrosis. Adipose tissue that exceeds their lipid storage capacity begins to release triglycerides into the bloodstream that can get stored in several organs, including the kidneys. The mechanisms underlying renal lipotoxicity involve intracellular lipid accumulation and organelle dysfunction, which trigger oxidative stress and inflammation that consequently result in insulin resistance and albuminuria. However, the specific pathways involved in renal lipotoxicity have not yet been fully understood. We aimed to summarize the current knowledge on the mechanisms by which lipotoxicity affects the renal morphology and function in experimental models of obesity. The accumulation of fatty acids in tubular cells has been described as the main mechanism of lipotoxicity; however, lipids and their metabolism also affect the function and the survival of podocytes. In this review, we presented indication of mitochondrial, lysosomal and endoplasmic reticulum alterations involved in kidney damage caused by obesity. The kidney is vulnerable to lipotoxicity, and studies of the mechanisms underlying renal injury caused by obesity can help identify therapeutic targets to control renal dysfunction.
Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review.
Fonseca-Correa Jorge I,Correa-Rotter Ricardo
Frontiers in medicine
Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.
Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs.
Wang Meihui,Wang Zixu,Chen Yaoxing,Dong Yulan
International journal of molecular sciences
The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.
Diet and kidney disease: the role of dietary fatty acids.
Schreiner G F,Klahr S
Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)
Several general principles with respect to the role of the fatty acids in the progression of kidney disease have begun to emerge from the mass of observational detail. Interventions that increase renal exposure to prostaglandins of the E series appear to be beneficial. They include administration of prostaglandin analogues and dietary supplementation with their fatty acid precursor, linoleate. The beneficial effects may be attributed to preservation of renal blood flow and glomerular filtration, reduction in blood pressure, direct effects on the lipid composition and function of cell membranes, and immune suppression. Interventions that inhibit thromboxane and leukotriene production, such as omega-3 fatty acid supplementation of the diet or administration of enzyme or receptor inhibitors, are also protective. Prevention of vasoconstriction, inhibition of platelet activation, and regulation of cell proliferation and matrix production have all been implicated in the mediation of the observed retardation of sclerosis. Fish oil may have synergistic, suppressive effects on various parameters of immune activation. Essential fatty acid deficiency, of course, inhibits both prostaglandin E and thromboxane production, cancelling out the protective and injurious components of arachidonate oxidation. Yet, studies on its beneficial effects have revealed another aspect of eicosanoid metabolism, independent of cyclooxygenase and lipoxygenase activity, that appears to regulate monocyte migration into injured tissue. Dietary interruption of this pathway has proven protective to renal structure and function. Alterations in lipid metabolism may represent a common, mediating pathway of glomerular and interstitial susceptibility to progressive sclerosis in the kidney. The process appears to be amenable to manipulation by pharmacologic or dietary modulation of fatty acid metabolism. Eicosanoid metabolites and tissue-leukocyte signaling are two mechanisms by which lipid alterations can affect renal function. There are doubtless many others awaiting elucidation. Delineation of all the mechanisms whereby fatty acid metabolism can contribute to progressive kidney injury may provide a useful model for the examination of progressive sclerosis affecting other tissues subsequent to immune, vascular, or metabolic injury.
Lipid abnormalities and renal disease: is dyslipidemia a predictor of progression of renal disease?
Crook Errol D,Thallapureddy Anantha,Migdal Stephen,Flack John M,Greene Eddie L,Salahudeen Abdullah,Tucker John K,Taylor Herman A
The American journal of the medical sciences
Dyslipidemia is a cardiovascular disease (CVD) risk factor that is associated with enhanced atherosclerosis and plaque instability. Renal insufficiency is associated with abnormalities in lipoprotein metabolism in both the early and the advanced stages of chronic renal failure. These include alterations in apolipoprotein A (apo A)- and B- containing lipoproteins, high-density lipoproteins, and triglycerides. In animal models, these alterations in lipid metabolism and action lead to macrophage activation and infiltration in the kidney with resultant tubulointerstitial and endothelial cell injury. Limited data in humans suggest that, in addition to contributing to CVD, dyslipidemia may be a risk factor for the progression of renal disease. The effects of dyslipidemia on the kidney are mainly observed in those with other risk factors for renal disease progression such as hypertension, diabetes, and proteinuria. Renal disease is a strong risk factor for CVD and African Americans have high rates of renal disease. Therefore, examining the effects of dyslipidemia on the development or progression or renal disease will be an important question for the Jackson Heart Study and is the topic of this review.
The potential role of sterol regulatory element binding protein transcription factors in renal injury.
Szolkiewicz Marek,Chmielewski Michal,Nogalska Anna,Stelmanska Ewa,Swierczynski Julian,Rutkowski Boleslaw
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation
The disturbed lipid metabolism is a permanent finding in renal failure. It is supposed to be a main reason for the accelerated atherosclerosis and high cardiovascular and cerebrovascular mortality of patients with renal failure. Sterol regulatory element binding proteins (SREBPs) are the transcription factors involved in the regulation of lipid homeostasis. They are responsible for the transcription activation of genes associated with the synthesis of fatty acids, triglycerides, and cholesterol. SREBP-1 gene expression in adipose tissue and SREBP-2 in liver are significantly elevated in renal failure. This is accompanied with the up-regulation of genes encoding enzymes of both fatty acids and cholesterol synthesis and significant serum lipid enhancement. Moreover, it has been shown that a destructive accumulation of lipids in the kidney structures is associated with enhanced kidney SREBP gene expression and increased lipid production. This was found even in the absence of any abnormalities in serum lipids. One may suppose that SREBP transcription factors play an important role in disturbed lipid metabolism in renal failure.
HDL metabolism and activity in chronic kidney disease.
Vaziri Nosratola D,Navab Mohamad,Fogelman Alan M
Nature reviews. Nephrology
Chronic kidney disease (CKD) is associated with development of atherosclerosis and premature death from cardiovascular disease. The predisposition of patients with CKD to atherosclerosis is driven by inflammation, oxidative stress and dyslipidemia, all of which are common features of this condition. Markers of dyslipidemia in patients with advanced CKD are impaired clearance and heightened oxidation of apolipoprotein-B-containing lipoproteins and their atherogenic remnants, and a reduction of the plasma concentration, antioxidant, and anti-inflammatory properties of high-density lipoprotein (HDL). Studies in animal models of CKD indicate that the disease promotes lipid accumulation in the artery wall and kidney, leading to atherosclerosis, glomerulosclerosis and tubulointerstitial injury. These effects seem to be mediated by an increased cellular influx of lipids, elevated cellular production and reduced cellular catabolism of fatty acids, and impaired antioxidant, anti-inflammatory and reverse lipid transport properties of HDL. Available pharmacological therapies have been largely ineffective in ameliorating oxidative stress, inflammation, HDL deficiency and/or dysfunction, and the associated atherosclerosis and cardiovascular disease in patients with end-stage renal disease. This Review aims to provide an overview of the mechanisms and consequences of CKD-induced HDL deficiency and dysfunction.
Renal lipid metabolism and lipotoxicity.
Bobulescu Ion Alexandru
Current opinion in nephrology and hypertension
PURPOSE OF REVIEW:Lipid accumulation in nonadipose tissues is increasingly recognized to contribute to organ injury through a process termed lipotoxicity, but whether this process occurs in the kidney is still uncertain. This article briefly summarizes the normal role of lipids in renal physiology and the current evidence linking excess lipids and lipotoxicity to renal dysfunction. RECENT FINDINGS:Evidence suggesting that renal lipid accumulation and lipotoxicity may lead to kidney dysfunction has mounted significantly over recent years. Abnormal renal lipid content has been described in a number of animal models and has been successfully manipulated using pharmacologic or genetic strategies. There is some heterogeneity among studies with regard to the mechanisms, consequences, and localization of lipid accumulation in the kidney, explainable at least in part by inherent differences between animal models. The relevance of these findings for human pathophysiology remains to be established. SUMMARY:Current knowledge on renal lipid physiology and pathophysiology is insufficient, but provides a strong foundation and incentive for further exploration. The future holds significant challenges in this area, especially with regard to applicability of research findings to the human kidney in vivo, but also the opportunity to transform our understanding of an array of kidney disorders.
Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes.
Nosadini R,Tonolo G
Nutrition, metabolism, and cardiovascular diseases : NMCD
Oxidized lipids initiate and modulate the inflammatory cellular events in the arterial wall and the formation of macrophage foam cells. CD36 mediates the cellular uptake of ox-LDL through its recognition of specific truncated fatty acid moieties and oxidized phosphatidylcholine. Evidence has been reported that chemokine CXCL16, rather than CD36, is the main scavenger receptor in human podocytes mediating the uptake of ox-LDL. Ox-LDL induces loss of nephrin expression from cultured podocytes. It has been recently shown that nephrin once phosphorilated associates with PI3K and stimulates the Akt dependent signaling. This pathway plays a critical role in nephrin-actin-dependent cytoskeleton activation and remodeling, in the control of protein trafficking and in podocyte survival. An enhanced FFA uptake by podocytes is mediated by increased C36 scavenger receptor expression, together with a decrease of betaoxidation and in turn intracellular lipid accumulation. Accumulated FFA that is trapped into the mitochondrial matrix leads to mitochondrial ROS production, lipid peroxidation and mitochondrial damage and dysfunction. A disturbed transport and oxidation of FFA, paralleled by an impaired antioxidant response, damages podocyte structure and leads to glomerulopathy in early stages of nephrosis. Increased triglyceride synthesis and ox-and glycated LDL uptake by mesangial cells may also contribute to determine diabetic glomerulopathy. Oxidative processes are pivotal events in injury to renal tubular and epithelial cells exposed to ox-LDL. Notably CXCL16 are the main receptors for the uptake of ox-LDL in podocytes, whereas CD36 plays this role in tubular renal cells. In overt type 2 diabetes Ox-LDL and FFA damage podocyte function, SD-podocyte structure and tubulointerstitial tissue, at least partially, through different pathogenetic mechanisms. Further studies are needed to investigate the role of Ox-LDL and FFA on renal complications in obese, insulin resistant patients before the development of diabetes. The aim of the present review is to briefly elucidate the patterns of systemic lipid metabolism and the individual effects of lipotoxicity at glomerular and tubular level in the kidney of overt type 2 diabetic patients. These findings better elucidate our knowledge of diabetic glomerulopathy, beside and along with previous findings, in vivo and in vitro, on ox-LDL and FFA effects in mesangial cells.
Bench-to-bedside review: Ventilation-induced renal injury through systemic mediator release--just theory or a causal relationship?
Kuiper Jan Willem,Vaschetto Rosanna,Della Corte Francesco,Plötz Frans B,Groeneveld A B Johan
Critical care (London, England)
We review the current literature on the molecular mechanisms involved in the pathogenesis of acute kidney injury induced by plasma mediators released by mechanical ventilation. A comprehensive literature search in the PubMed database was performed and articles were identified that showed increased plasma levels of mediators where the increase was solely attributable to mechanical ventilation. A subsequent search revealed articles delineating the potential effects of each mediator on the kidney or kidney cells. Limited research has focused specifically on the relationship between mechanical ventilation and acute kidney injury. Only a limited number of plasma mediators has been implicated in mechanical ventilation-associated acute kidney injury. The number of mediators released during mechanical ventilation is far greater and includes pro- and anti-inflammatory mediators, but also mediators involved in coagulation, fibrinolysis, cell adhesion, apoptosis and cell growth. The potential effects of these mediators is pleiotropic and include effects on inflammation, cell recruitment, adhesion and infiltration, apoptosis and necrosis, vasoactivity, cell proliferation, coagulation and fibrinolysis, transporter regulation, lipid metabolism and cell signaling. Most research has focused on inflammatory and chemotactic mediators. There is a great disparity of knowledge of potential effects on the kidney between different mediators. From a theoretical point of view, the systemic release of several mediators induced by mechanical ventilation may play an important role in the pathophysiology of acute kidney injury. However, evidence supporting a causal relationship is lacking for the studied mediators.
Glycosphingolipids and kidney disease.
Mather Andrew R,Siskind Leah J
Advances in experimental medicine and biology
Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.
Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis.
Keane William F,Tomassini Joanne E,Neff David R
Journal of atherosclerosis and thrombosis
Cardiovascular disease is increased in patients with chronic kidney disease (CKD) and is the principle cause of morbidity and mortality in these patients. In patients with stage 5 CKD, structural changes in the myocardium have been implicated as the principle cardiovascular processes leading to this increase in morbidity and mortality, while atherosclerotic events including acute myocardial infarction and strokes are responsible for approximately 10-15% of cardiovascular deaths. Dyslipidemia is common in CKD patients and is usually not characterized by elevated cholesterol levels, except in patients with marked proteinuria. Increased triglyceride levels in conjunction with decreased high-density lipoprotein levels are the commonest qualitative abnormality. Characteristically, abnormalities in the metabolism of apolipoprotein (apo) B-containing lipoproteins have been described, including both gut derived (apoB-48) as well as those produced by hepatic synthesis (apoB-100). A decrease in enzymatic delipidation as well as reduced receptor removal of these lipoproteins both contribute to the increased levels of these apo-B-containing particles and their remnants (which are believed to be highly atherogenic). Abnormalities in the metabolism of apoA-containing lipoproteins are also present and these changes contribute to the lower levels of HDL seen. Qualitative abnormalities of these HDL particles may be associated with cellular oxidative injury and contribute to a pro-inflammatory, pro-thrombotic milieu that is frequently present in CKD patients.
Metabolism, energetics, and lipid biology in the podocyte - cellular cholesterol-mediated glomerular injury.
Merscher Sandra,Pedigo Christopher E,Mendez Armando J
Frontiers in endocrinology
Chronic kidney disease (CKD) is associated with a high risk of death. Dyslipidemia is commonly observed in patients with CKD and is accompanied by a decrease in plasma high-density lipoprotein, and an increase in plasma triglyceride-rich lipoproteins and oxidized lipids. The observation that statins may decrease albuminuria but do not stop the progression of CKD indicates that pathways other than the cholesterol synthesis contribute to cholesterol accumulation in the kidneys of patients with CKD. Recently, it has become clear that increased lipid influx and impaired reverse cholesterol transport can promote glomerulosclerosis, and tubulointerstitial damage. Lipid-rafts are cholesterol-rich membrane domains with important functions in regulating membrane fluidity, membrane protein trafficking, and in the assembly of signaling molecules. In podocytes, which are specialized cells of the glomerulus, they contribute to the spatial organization of the slit diaphragm (SD) under physiological and pathological conditions. The discovery that podocyte-specific proteins such as podocin can bind and recruit cholesterol contributing to the formation of the SD underlines the importance of cholesterol homeostasis in podocytes and suggests cholesterol as an important regulator in the development of proteinuric kidney disease. Cellular cholesterol accumulation due to increased synthesis, influx, or decreased efflux is an emerging concept in podocyte biology. This review will focus on the role of cellular cholesterol accumulation in the pathogenesis of kidney diseases with a focus on glomerular diseases.
Free Fatty acids and their metabolism affect function and survival of podocytes.
Sieber Jonas,Jehle Andreas Werner
Frontiers in endocrinology
Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.
Kidneys: key modulators of high-density lipoprotein levels and function.
Yang Haichun,Fogo Agnes B,Kon Valentina
Current opinion in nephrology and hypertension
PURPOSE OF REVIEW:The review will examine advances in our understanding of the role kidneys play in high-density lipoprotein (HDL) metabolism and the effect on levels, composition, and function of HDL particles. RECENT FINDINGS:Components of the HDL particles can cross the glomerular filtration barrier. Some of these components, including apolipoproteins and enzymes involved in lipid metabolism, are taken up by the proximal tubule and degraded, modified, salvaged/returned to the circulation, or lost in the urine. Injury of the glomerular capillaries or tubules can affect these intrarenal processes and modify HDL. Changes in the plasma and urine levels of HDL may be novel markers of kidney damage or mechanism(s) of kidney disease. SUMMARY:The kidneys have a significant role in the metabolism of individual HDL components, which in turn modulate HDL levels, composition, and functionality of HDL particles. These intrarenal effects may be useful markers of kidney damage and have consequences on kidney-related perturbations in HDL.
The role of short-chain fatty acids in kidney injury induced by gut-derived inflammatory response.
Huang Wei,Zhou Luping,Guo Hengli,Xu Youhua,Xu Yong
Metabolism: clinical and experimental
It has been found that several circulating metabolites derived from gut microbiota fermentation associate with a systemic immuno-inflammatory response and kidney injury, which has been coined the gut-kidney axis. Recent evidence has suggested that short-chain fatty acids (SCFAs), which are primarily originated from fermentation of dietary fiber in the gut, play an important role in regulation of immunity, blood pressure, glucose and lipid metabolism, and seem to be the link between microbiota and host homeostasis. In addition to their important role as fuel for colonic epithelial cells, SCFAs also modulate different cell signal transduction processes via G-protein coupled receptors, and act as epigenetic regulators by the inhibition of histone deacetylase and as potential mediators involved in the autophagy pathway. Though controversial, an intimate connection between SCFAs and kidney injury has been revealed, suggesting that SCFAs may act as new therapeutic targets of kidney injury. This review is intended to provide an overview of the impact of SCFAs and the potential link to kidney injury induced by gut-derived inflammatory response.
CD36 in chronic kidney disease: novel insights and therapeutic opportunities.
Yang Xiaochun,Okamura Daryl M,Lu Xifeng,Chen Yaxi,Moorhead John,Varghese Zac,Ruan Xiong Z
Nature reviews. Nephrology
CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates the binding and cellular uptake of long-chain fatty acids, oxidized lipids and phospholipids, advanced oxidation protein products, thrombospondin and advanced glycation end products, and has roles in lipid accumulation, inflammatory signalling, energy reprogramming, apoptosis and kidney fibrosis. Renal CD36 is mainly expressed in tubular epithelial cells, podocytes and mesangial cells, and is markedly upregulated in the setting of chronic kidney disease (CKD). As fatty acids are the preferred energy source for proximal tubule cells, a reduction in fatty acid oxidation in CKD affects kidney lipid metabolism by disrupting the balance between fatty acid synthesis, uptake and consumption. The outcome is intracellular lipid accumulation, which has an important role in the pathogenesis of kidney fibrosis. In experimental models, antagonist blockade or genetic knockout of CD36 prevents kidney injury, suggesting that CD36 could be a novel target for therapy. Here, we discuss the regulation and post-translational modification of CD36, its role in renal pathophysiology and its potential as a biomarker and as a therapeutic target for the prevention of kidney fibrosis.
Ferroptosis and necroinflammation, a yet poorly explored link.
Cell death and differentiation
Ferroptosis is a non-apoptotic form of cell death characterized by overwhelming iron-dependent lipid peroxidation, which contributes to a number of pathologies, most notably tissue ischemia/reperfusion injury, neurodegeneration and cancer. Cysteine availability, glutathione biosynthesis, polyunsaturated fatty acid metabolism and modulation of the phospholipidome are the key events of this necrotic cell death pathway. Non-enzymatic and enzymatic lipoxygenase (LOX)-mediated lipid peroxidation of lipid bilayers is efficiently counteracted by the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis. Preliminary studies suggest that bursting ferroptotic cells release pro-inflammatory damage-associated molecular patterns (DAMPs) that trigger the innate immune system as exemplified by diseased kidney and brain tissues where ferroptosis contributes to organ demise in a predominant manner. The GSH/GPX4 node is known to control the activities of LOX and prostaglandin-endoperoxide synthase (PTGS) via the so-called peroxide tone. Since LOX and PTGS products do have pro- and anti-inflammatory effects, one may speculate that these enzymes contribute to the ferroptotic process on several levels in cell-autonomous and non-autonomous ways. Hence, this review provides the reader with an outline on what is currently known about the link between ferroptosis and necroinflammation and discusses critical events that may alert the innate immune system in early phases when cells become sensitized towards ferroptosis.
Statins: Adverse reactions, oxidative stress and metabolic interactions.
Liu Aimei,Wu Qinghua,Guo Jingchao,Ares Irma,Rodríguez José-Luis,Martínez-Larrañaga María-Rosa,Yuan Zonghui,Anadón Arturo,Wang Xu,Martínez María-Aránzazu
Pharmacology & therapeutics
Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primary focus of this article is to summarize the research progress associated with oxidative stress as a plausible mechanism for statin-induced toxicity, as well as its metabolic interactions. This review summarizes the research conducted over the past five years into the production of reactive oxygen species, oxidative stress as a result of statin treatments, and their correlation with statin-induced toxicity and metabolism. Statin-induced metabolism involves various CYP450 enzymes, which provide potential sites for statin-induced oxidative stress, and these metabolic factors are also reviewed. The therapeutics of a variety of compounds against statin-induced organ damage based on their anti-oxidative effects is also discussed to further understand the role of oxidative stress in statin-induced toxicity. This review sheds new light on the critical roles of oxidative stress in statin-induced toxicity and prevention of this oxidative damage, as well as on the contradictions and unknowns that still exist regarding statin toxicity and the cellular effects in terms of organ injury and cell signaling pathways.
What we need to know about lipid-associated injury in case of renal ischemia-reperfusion.
Erpicum Pauline,Rowart Pascal,Defraigne Jean-Olivier,Krzesinski Jean-Marie,Jouret François
American journal of physiology. Renal physiology
Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion injury (IRI) is due to the restriction of renal blood flow, rapidly leading to a metabolic switch toward anaerobic conditions. Subsequent unbalance between energy demand and oxygen/nutrient delivery compromises kidney cell functions, resulting in a complex inflammatory cascade including the production of reactive oxygen species (ROS). Renal IRI especially involves lipid accumulation. Lipid peroxidation is one of the major events of ROS-associated tissue injury. Here, we briefly review the current knowledge of renal cell lipid metabolism in normal and ischemic conditions. Next, we focus on renal lipid-associated injury, with emphasis on its mechanisms and consequences during the course of IRI. Finally, we discuss preclinical observations aiming at preventing and/or attenuating lipid-associated IRI.
PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation.
Cheng Ching-Feng,Ku Hui-Chen,Lin Heng
International journal of molecular sciences
Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1α in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1α overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1α increased hepatic fatty acid oxidation and decreased triacylglycerol storage and secretion in vivo and in vitro. In this review, we discuss recent studies showing that PGC-1α may regulate mitochondrial fusion⁻fission homeostasis and affect the renal function in acute or chronic kidney injury. Furthermore, PGC-1α is an emerging protein with a biphasic role in cancer, acting both as a tumor suppressor and a tumor promoter and thus representing a new and unresolved topic for cancer biology studies. In summary, this review paper demonstrates that PGC-1α plays a central role in coordinating the gene expression of key components of mitochondrial biogenesis and as a critical metabolic regulator in many vital organs, including white and brown adipose tissue, skeletal muscle, heart, liver, and kidney.
The farnesoid X receptor: a potential target for expanding the therapeutic arsenal against kidney disease.
Masaoutis Christos,Theocharis Stamatios
Expert opinion on therapeutic targets
INTRODUCTION:Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease. Areas covered: Following a summary of FXR's physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date. Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.
Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease.
Current diabetes reports
PURPOSE OF REVIEW:The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression. RECENT FINDINGS:Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.
Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities.
Opazo-Ríos Lucas,Mas Sebastián,Marín-Royo Gema,Mezzano Sergio,Gómez-Guerrero Carmen,Moreno Juan Antonio,Egido Jesús
International journal of molecular sciences
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
C1q/TNF-related Protein 1, a Multifunctional Adipokine: An Overview of Current Data.
Janowska Joanna Dorota
The American journal of the medical sciences
The present review aimed to present the research highlights on C1q/TNF-related protein 1 (CTRP1), a member of the recently discovered family of highly conserved adiponectin paralog proteins, C1q tumor necrosis factor-related proteins. CTRP1 plays an important role in regulating body energy homeostasis and sensitivity to insulin. Studies on animal models have shown that it lowers the concentration of glucose. Elevated concentrations of CTRP1 reduce weight gain and diet-induced insulin resistance. CTRP1 limits the extent of ischemia-reperfusion injury in acute myocardial infarction. It inhibits platelet aggregation by blocking von Willebrand factor binding to collagen. In patients with chronic kidney disease, an increase in CTRP1 levels is associated with a lesser degree of disease progression. CTRP1 stimulates aldosterone synthesis in the adrenal cortex by affecting aldosterone synthase expression. In dehydration, an increase in CTRP1 concentration helps to maintain normotension. It participates in processes related to the proliferation and maturation of chondrocytes. It also promotes atherosclerosis, and a surge in its concentration is correlated with a higher cardiovascular risk in patients with coronary atherosclerosis. In vascular smooth muscle cells, it induces the expression of proinflammatory cytokines. An increase in CTRP1 levels is correlated with the progression of the neoplastic process in patients with glioblastoma.
Organelle Stress and Crosstalk in Kidney Disease.
Organelles play important roles in maintaining cellular homeostasis. Organelle stress responses, especially in mitochondria, endoplasmic reticula (ER), and primary cilia, are deeply involved in kidney disease pathophysiology. Mitochondria are the center of energy production in most eukaryotic cells. Renal proximal tubular cells are highly energy demanding and abundant in mitochondria. Mitochondrial dysfunctions in association with energy metabolism alterations produce reactive oxygen species and promote inflammation in proximal tubular cells, resulting in progression of kidney disease. The ER play critical roles in controlling protein quality. Unfolded protein response (UPR) pathways are the adaptive response to ER stress for maintaining protein homeostasis. UPR pathway dysregulation under pathogenic ER stress often occurs in glomerular and tubulointerstitial cells and promotes progression of kidney disease. The primary cilia sense extracellular signals and maintain calcium homeostasis in cells. Dysfunction of the primary cilia in autosomal dominant polycystic kidney disease reduces the calcium concentration in proximal tubular cells, leading to increased cell proliferation and retention of cyst fluid. In recent years, the direct interaction at membrane contact sites has received increased attention in association with the development of imaging technologies. The part of the ER that is directly connected to mitochondria is termed the mitochondria-associated ER membrane (MAM), which regulates calcium homeostasis and phospholipid metabolism in cells. Disruption of MAM integrity collapses cellular homeostasis and leads to diseases such as diabetes and Alzheimer disease. This review summarizes recent research on organelle stress and crosstalk, and their involvement in kidney disease pathophysiology. In addition, potential treatment options that target organelle stress responses are discussed.
The potential roles of chitosan oligosaccharide in prevention of kidney injury in obese and diabetic conditions.
Sutthasupha Prempree,Lungkaphin Anusorn
Food & function
Obesity is closely associated with insulin resistance (IR). The most likely links between the two are obesity-mediated systemic low-grade chronic inflammation, endoplasmic reticulum stress and mitochondrial dysfunction, which are all known to contribute to the development of type 2 diabetes (T2DM) and eventually diabetic nephropathy (DN). Chitosan oligosaccharide (COS) is an oligomer of chitosan prepared by the deacetylation of chitin commonly found in exoskeletons of crustaceans such as shrimp and crab as well as the cell walls of fungi. COS has various biological effects including lipid lowering, anti-inflammation, anti-diabetes, and anti-oxidant effects. Therefore, COS is a potential new therapeutic agent for treatment of the obesity-induced DN condition. It is an abundant natural polymer and therefore freely available. This review includes information regarding the relationship between obesity, IR, T2DM, and DN as well as the potential usefulness of COS in controlling lipid and cholesterol metabolism, T2DM and kidney injury models in both in vivo and in vitro studies. However, evidence is limited regarding the effect of COS on the DN model. Further studies, especially in obesity-induced DN, are needed to support the mechanisms proposed in this review.
Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities.
Lin Pei-Hui,Duann Pu
Frontiers in physiology
To excrete body nitrogen waste and regulate electrolyte and fluid balance, the kidney has developed into an energy factory with only second to the heart in mitochondrial content in the body to meet the high-energy demand and regulate homeostasis. Energy supply from the renal mitochondria majorly depends on lipid metabolism, with programed enzyme systems in fatty acid β-oxidation and Krebs cycle. Renal mitochondria integrate several metabolic pathways, including AMPK/PGC-1α, PPARs, and CD36 signaling to maintain energy homeostasis for dynamic and static requirements. The pathobiology of several kidney disorders, including diabetic nephropathy, acute and chronic kidney injuries, has been primarily linked to impaired mitochondrial bioenergetics. Such homeostatic disruption in turn stimulates a pathological adaptation, with mitochondrial enzyme system reprograming possibly leading to dyslipidemia. However, this alteration, while rescuing oncotic pressure deficit secondary to albuminuria and dissipating edematous disorder, also imposes an ominous lipotoxic consequence. Reprograming of lipid metabolism in kidney injury is essential to preserve the integrity of kidney mitochondria, thereby preventing massive collateral damage including excessive autophagy and chronic inflammation. Here, we review dyslipidemia in kidney disorders and the most recent advances on targeting mitochondrial energy metabolism as a therapeutic strategy to restrict renal lipotoxicity, achieve salutary anti-edematous effects, and restore mitochondrial homeostasis.
Nuclear receptors in the kidney during health and disease.
Libby Andrew E,Jones Bryce,Lopez-Santiago Isabel,Rowland Emma,Levi Moshe
Molecular aspects of medicine
Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis-many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression.
Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine.
Cioccari Luca,Luethi Nora,Masoodi Mojgan
Frontiers in immunology
A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients' inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.
Metabolic Alterations in SARS-CoV-2 Infection and Its Implication in Kidney Dysfunction.
Andrade Silva Magaiver,da Silva Ana Ruth Paolinetti Alves,do Amaral Mariana Abrantes,Fragas Matheus Garcia,Câmara Niels Olsen Saraiva
Frontiers in physiology
Clinical strategies focusing on pathogen elimination are expected in an infectious-disease outbreak, such as the severe coronavirus disease 2019 (COVID-19), to avoid organ dysfunction. However, understanding the host response to viral infection is crucial to develop an effective treatment to optimize the patient's conditions. The pathogenic viruses can promote metabolic changes during viral infection, favoring its survival, altering cell phenotype and function, and causing sustained inflammation and tissue injury. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, provokes systemic and cell metabolic changes and possibly altering lipid and glucose metabolism. Besides severe acute respiratory syndrome (SARS), SARS-CoV-2 can cause acute kidney injury, which has been associated with the severity of the disease. Although it is not clear the mechanisms whereby SARS-CoV-2 induces kidney dysfunction, it is known that the virus presents kidney tropism, namely, podocytes and proximal tubular epithelial cells. Changes in renal cell metabolism and systemic metabolic disorders are important events in kidney injury progression. Here, we explored the metabolism and its interface with SARS-CoV-2 infection and raised the perspective on metabolism disturbances as a critical event to kidney dysfunction in COVID-19.
Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis.
Wlazlo Ewa,Mehrad Borna,Morel Laurence,Scindia Yogesh
Frontiers in medicine
Nephritis is a common manifestation of systemic lupus erythematosus, a condition associated with inflammation and iron imbalance. Renal tubules are the work horse of the nephron. They contain a large number of mitochondria that require iron for oxidative phosphorylation, and a tight control of intracellular iron prevents excessive generation of reactive oxygen species. Iron supply to the kidney is dependent on systemic iron availability, which is regulated by the hepcidin-ferroportin axis. Most of the filtered plasma iron is reabsorbed in proximal tubules, a process that is controlled in part by iron regulatory proteins. This review summarizes tubulointerstitial injury in lupus nephritis and current understanding of how renal tubular cells regulate intracellular iron levels, highlighting the role of iron imbalance in the proximal tubules as a driver of tubulointerstitial injury in lupus nephritis. We propose a model based on the dynamic ability of iron to catalyze reactive oxygen species, which can lead to an accumulation of lipid hydroperoxides in proximal tubular epithelial cells. These iron-catalyzed oxidative species can also accentuate protein and autoantibody-induced inflammatory transcription factors leading to matrix, cytokine/chemokine production and immune cell infiltration. This could potentially explain the interplay between increased glomerular permeability and the ensuing tubular injury, tubulointerstitial inflammation and progression to renal failure in LN, and open new avenues of research to develop novel therapies targeting iron metabolism.
Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications.
Stasi Alessandra,Franzin Rossana,Fiorentino Marco,Squiccimarro Enrico,Castellano Giuseppe,Gesualdo Loreto
International journal of molecular sciences
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.
Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function.
Brennan Eoin,Kantharidis Phillip,Cooper Mark E,Godson Catherine
Nature reviews. Nephrology
Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.
PPARγ and TGFβ-Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys.
Kökény Gábor,Calvier Laurent,Hansmann Georg
International journal of molecular sciences
Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.
cGAS‒STING signaling and function in metabolism and kidney diseases.
Bai Juli,Liu Feng
Journal of molecular cell biology
The cyclic GMP‒AMP synthase (cGAS)‒stimulator of interferon genes (STING) signaling pathway senses the presence of cytosolic DNA and, in turn, triggers downstream signaling to induce the expression of inflammatory and type I interferon genes in immune cells. Whereas the innate immune function of the cGAS‒STING pathway is well studied over the past years, emerging evidence suggests that this signaling pathway may have additional functions beyond innate immune surveillance. Consistent with this notion, dysregulation of the cGAS‒STING signaling pathway in adipocytes, hepatocytes, and renal proximal tubule epithelial cells are associated with metabolic dysfunction, impaired energy homeostasis, and kidney diseases. In this review, we summarize current understanding of the cGAS‒STING pathway in several metabolic diseases such as obesity, insulin resistance, alcoholic and nonalcoholic fatty liver diseases, as well as acute kidney injury and chronic kidney disease. We also review the interaction between the cGAS‒STING pathway and lipid metabolism. Lastly, we discuss potential mechanisms by which cGAS‒STING signaling regulates metabolism and point toward future avenues of research targeting the cGAS‒STING pathway as possible means to treat common metabolic disorders.
Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy?
Wang Muyun,Wang Kun,Liao Ximing,Hu Haiyang,Chen Liangzhi,Meng Linlin,Gao Wei,Li Qiang
Frontiers in pharmacology
Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia-reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders.
Mechanisms and pharmacological applications of ferroptosis: a narrative review.
Annals of translational medicine
OBJECTIVE:We aimed at comprehensively analyzing ferroptosis regulation and its potential role in the treatment of associated diseases. BACKGROUND:Ferroptosis is a recently discovered form of cell death that involves small molecule-induced oxidative cell death. This process is usually accompanied by large amounts of iron accumulation and lipid peroxidation. Ferroptosis inducers directly or indirectly affect glutathione peroxidase (GPXs) through different pathways. Disturbances in GPXs result in suppressed cellular antioxidant capacities, accumulation of lipid reactive oxygen species (ROS) and oxidative cell death. It has been reported that ferroptosis is closely associated with the pathophysiological processes of many diseases, including tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury and iron metabolism diseases among others. METHODS:First, we reviewed the mechanisms of ferroptosis, with emphasis on the characteristics and functions of ferroptosis in multiple pathways. Then, inducers and inhibitors of ferroptosis were reviewed, and their mechanisms of action elucidated. Finally, ferroptosis-associated pathophysiological processes of various diseases were reviewed. CONCLUSIONS:Ferroptosis is associated with the occurrence and development of various diseases. Elucidation of the mechanisms involved in ferroptosis will inform new therapeutic targets and strategies for these diseases.
The Updates of Podocyte Lipid Metabolism in Proteinuric Kidney Disease.
Kidney diseases (Basel, Switzerland)
BACKGROUND:Podocytes, functionally specialized and terminally differentiated glomerular visceral epithelial cells, are critical for maintaining the structure and function of the glomerular filtration barrier. Podocyte injury is considered as the most important early event contributing to proteinuric kidney diseases such as obesity-related renal disease, diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Although considerable advances have been made in the understanding of mechanisms that trigger podocyte injury, cell-specific and effective treatments are not clinically available. SUMMARY:Emerging evidence has indicated that the disorder of podocyte lipid metabolism is closely associated with various proteinuric kidney diseases. Excessive lipid accumulation in podocytes leads to cellular dysfunction which is defined as lipotoxicity, a phenomenon characterized by mitochondrial oxidative stress, actin cytoskeleton remodeling, insulin resistance, and inflammatory response that can eventually result in podocyte hypertrophy, detachment, and death. In this review, we summarize recent advances in the understanding of lipids in podocyte biological function and the regulatory mechanisms leading to podocyte lipid accumulation in proteinuric kidney disease. KEY MESSAGES:Targeting podocyte lipid metabolism may represent a novel therapeutic strategy for patients with proteinuric kidney disease.
The Emerging Role of Ferroptosis in Liver Diseases.
Chen Si,Zhu Jun-Yao,Zang Xin,Zhai Yong-Zhen
Frontiers in cell and developmental biology
Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.
Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential.
Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.
Organelle Stress and Metabolic Derangement in Kidney Disease.
International journal of molecular sciences
Advanced multiomics analysis has revealed novel pathophysiological mechanisms in kidney disease. In particular, proteomic and metabolomic analysis shed light on mitochondrial dysfunction (mitochondrial stress) by glycation in diabetic or age-related kidney disease. Further, metabolic damage often results from organelle stress, such as mitochondrial stress and endoplasmic reticulum (ER) stress, as well as interorganelle communication, or "organelle crosstalk", in various kidney cells. These contribute to progression of the disease phenotype. Aberrant tubular mitochondrial lipid metabolism leads to tubular inflammation and fibrosis. This review article summarizes updated evidence regarding organelle stress, organelle crosstalk, and metabolic derangement in kidney disease.
Fatty Acid β-Oxidation in Kidney Diseases: Perspectives on Pathophysiological Mechanisms and Therapeutic Opportunities.
Frontiers in pharmacology
The kidney is a highly metabolic organ and requires a large amount of ATP to maintain its filtration-reabsorption function, and mitochondrial fatty acid β-oxidation serves as the main source of energy to meet its functional needs. Reduced and inefficient fatty acid β-oxidation is thought to be a major mechanism contributing to kidney diseases, including acute kidney injury, chronic kidney disease and diabetic nephropathy. PPARα, AMPK, sirtuins, HIF-1, and TGF-β/SMAD3 activation have all been shown to play key roles in the regulation of fatty acid β-oxidation in kidney diseases, and restoration of fatty acid β-oxidation by modulation of these molecules can ameliorate the development of such diseases. Here, we disentangle the lipid metabolism regulation properties and potential mechanisms of mesenchymal stem cells and their extracellular vesicles, and emphasize the role of mesenchymal stem cells on lipid metabolism. This review aims to highlight the important role of fatty acid β-oxidation in the progression of kidney diseases, and to explore the fatty acid β-oxidation effects and therapeutic potential of mesenchymal stem cells for kidney diseases.