Rutaecarpine alleviates inflammation and fibrosis by targeting CK2α in diabetic nephropathy.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus. During the progression of DN, the proliferation of glomerular mesangial cells (GMCs) leads to the deposition of excessive extracellular matrix (ECM) in the mesangial region, eventually resulting in glomerulosclerosis. Rutaecarpine (Rut), an alkaloid found in the traditional Chinese medicinal herb Fructus Evodiae (Euodia rutaecarpa (Juss.) Benth.), has many biological activities. However, its mechanism of action in DN remains unknown. This study used db/db mice and high glucose (HG)-treated mouse mesangial cells (SV40 MES-13) to evaluate the protective effects of Rut and underlying mechanisms on GMCs in DN. We found that Rut alleviated urinary albumin and renal function and significantly relieved renal pathological damage. In addition, Rut decreased the ECM production, and renal inflammation and suppressed the activation of TGF-β1/Smad3 and NF-κB signaling pathways in vitro and in vivo. Protein kinase CK2α (CK2α) was identified as the target of Rut by target prediction, molecular docking, and cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR). Furthermore, Rut could not continue to play a protective role in HG-treated SV40 cells after silencing CK2α. In summary, this study is the first to find that Rut can suppress ECM production and inflammation in HG-treated SV40 cells by inhibiting the activation of TGF-β1/Smad3 and NF-κB signaling pathways and targeting CK2α. Thus, Rut can potentially become a novel treatment option for DN.
10.1016/j.biopha.2024.117499
Proteomics and Incident Kidney Failure in Individuals With CKD: The African American Study of Kidney Disease and Hypertension and the Boston Kidney Biopsy Cohort.
Kidney medicine
Rationale & Objective:Individuals with chronic kidney disease (CKD) are at increased risk of morbidity and mortality, particularly as they progress to kidney failure. Identifying circulating proteins that underlie kidney failure development may guide the discovery of new targets for intervention. Study Design:Prospective cohort. Setting & Participants:703 African American Study of Kidney Disease and Hypertension (AASK) and 434 Boston Kidney Biopsy Cohort (BKBC) participants with baseline proteomics data. Exposures:Circulating proteins measured using SomaScan. Outcomes:Kidney failure, defined as dialysis initiation or kidney transplantation. Analytical Approach:Using adjusted Cox models, we studied associations of 6,284 circulating proteins with kidney failure risk separately in AASK and BKBC and meta-analyzed results. We then performed gene set enrichment analyses to identify underlying perturbations in biological pathways. In separate data sets with kidney-tissue level gene expression, we ascertained dominant regions of expression and correlated kidney tubular gene expression with fibrosis and estimated glomerular filtration rate (eGFR). Results:Over median follow-up periods of 8.8 and 3.1 years, 210 AASK (mean age: 55 years, 39% female, mean GFR: 46 mL/min/1.73 m) and 115 BKBC (mean age: 54 years, 47% female, mean eGFR: 51 mL/min/1.73 m) participants developed kidney failure, respectively. We identified 143 proteins that were associated with incident kidney failure, of which only 1 (Testican-2) had a lower risk. Notable proteins included those related to vascular permeability (endothelial cell-selective adhesion molecule), glomerulosclerosis (ephrin-A1), glomerular development (ephrin-B2), intracellular sorting/transport (vesicular integral-membrane protein VIP36), podocyte effacement (pigment epithelium-derived factor), complement activation (complement decay-accelerating factor), and fibrosis (ephrin-A1, ephrin-B2, and pigment epithelium-derived factor). Gene set enrichment analyses detected overrepresented pathways that could be related to CKD progression, such as ephrin signaling, cell-cell junctions, intracellular transport, immune response, cell proliferation, and apoptosis. At the kidney level, glomerular expression predominated for genes corresponding to circulating proteins of interest, and several gene expression levels were correlated with eGFR and/or fibrosis. Limitations:Possible residual confounding. Conclusions:Multimodal data identified proteins and pathways associated with the development of kidney failure.
10.1016/j.xkme.2024.100921
Curcumin ameliorates focal segmental glomerulosclerosis by inhibiting apoptosis and oxidative stress in podocytes.
Archives of biochemistry and biophysics
Focal segmental glomerulosclerosis (FSGS), a podocyte disease, is the leading cause of end-stage renal disease (ESRD). Nevertheless, the current effective treatment for FSGS is deficient. Curcumin (CUR) is a principal curcuminoid of turmeric, which is a member of the ginger family. Previous studies have shown that CUR has renoprotective effects. However, the mechanism of CUR in anti-FSGS is not clear. This study aimed to explore the mechanism of CUR against FSGS through a combination of network pharmacological methods and verification of experiments. The analysis identified 98 shared targets of CUR against FSGS, and these 98 targets formed a network of protein-protein interactions (PPI). Of these 98 targets, AKT1, TNF, IL-6, VEGFA, STAT3, MAPK3, HIF1A, CASP3, IL1B, and JUN were identified as the hub targets. Molecular docking suggested that the best binding to CUR is MAPK3 and AKT1. Apoptotic process and cell proliferation were identified as the main biological processes of CUR against FSGS by gene ontology (GO) analysis. The most enriched signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was the PI3K-AKT signaling pathway. Western blots and flow cytometry showed that CUR could inhibit adriamycin (ADR) induced apoptosis, oxidative stress damage, and attenuate podocyte epithelial-mesenchymal transition (EMT) by repressing the AKT signaling pathway. Collectively, our study demonstrates that CUR can attenuate apoptosis, oxidative stress damage, and EMT in FSGS in vitro. These results supply a compelling basis for future studies of CUR for the clinical treatment of FSGS.
10.1016/j.abb.2023.109728
Targeting ROCK1 in diabetic kidney disease: Unraveling mesangial fibrosis mechanisms and introducing myricetin as a novel antagonist.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetic kidney disease (DKD) stands as a pressing health challenge, with mesangial cell fibrosis identified as a pivotal hallmark leading to glomerular sclerosis. Gaining a deeper grasp on the molecular dynamics behind this can potentially introduce groundbreaking therapeutic avenues. Recent revelations from studies on ROCK1-deficient mice, which displayed resilience against high-fat diet (HFD)-induced glomerulosclerosis and mitochondrial fragmentation, spurred our hypothesis regarding ROCK1's potential role in mesangial cell fibrosis. Subsequent rigorous experiments corroborated our theory, highlighting the critical role of ROCK1 in orchestrating mesangial cell proliferation and fibrosis, especially in high-glucose settings. Mechanistically, ROCK1 inhibition led to a notable hindrance in the high-glucose-triggered MAPK signaling pathway, particularly emphasizing the ROCK1/ERK/P38 axis. To translate this understanding into potential therapeutic interventions, we embarked on a comprehensive drug screening journey. Leveraging molecular modeling techniques, Myricetin surfaced as an efficacious inhibitor of ROCK1. Dose-dependent in vitro assays substantiated Myricetin's prowess in curtailing mesangial cell proliferation and fibrosis via ROCK1/ERK/P38 pathway. In vivo verifications paralleled these findings, with Myricetin treatment resulting in significant renal function enhancements and diminished DKD pathological markers, all pivoted around the ROCK1/ERK/P38 nexus. These findings not only deepen our comprehension of DKD molecular underpinnings but also elevate ROCK1 to the pedestal of a promising therapeutic beacon. Concurrently, Myricetin is spotlighted as a potent natural contender, heralding a new era in DKD therapeutic design.
10.1016/j.biopha.2024.116208
The contribution of the sphingosine 1-phosphate signaling pathway to chronic kidney diseases: recent findings and new perspectives.
Pflugers Archiv : European journal of physiology
Chronic kidney disease (CKD) is a multifactorial condition with diverse etiologies, such as diabetes mellitus, hypertension, and genetic disorders, often culminating in end-stage renal disease (ESRD). A hallmark of CKD progression is kidney fibrosis, characterized by the excessive accumulation of extracellular matrix components, for which there is currently no effective anti-fibrotic therapy. Recent literature highlights the critical role of sphingosine 1-phosphate (S1P) signaling in CKD pathogenesis and renal fibrosis. This review provides an in-depth analysis of the latest findings on S1P metabolism and signaling in renal fibrosis and in specific CKDs, including diabetic nephropathy (DN), lupus nephritis (LN), focal segmental glomerulosclerosis (FSGS), Fabry disease (FD), and IgA nephropathy (IgAN). Emerging studies underscore the therapeutic potential of modulating S1P signaling with receptor modulators and inhibitors, such as fingolimod (FTY720) and more selective agents like ozanimod and cenerimod. Additionally, the current knowledge about the effects of established kidney protective therapies such as glucocorticoids and SGLT2 and ACE inhibitors on S1P signaling will be summarized. Furthermore, the review highlights the potential role of S1P as a biomarker for disease progression in CKD models, particularly in Fabry disease and diabetic nephropathy. Advanced technologies, including spatial transcriptomics, are further refining our understanding of S1P's role within specific kidney compartments. Collectively, these insights emphasize the need for continued research into S1P signaling pathways as promising targets for CKD treatment strategies.
10.1007/s00424-024-03029-5
Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway.
Frontiers in pharmacology
Focal segmental glomerulosclerosis (FSGS) is a common clinical condition with manifestations of nephrotic syndrome and fibrosis of the glomeruli and interstitium. Yi-Shen-Hua-Shi (YSHS) granule has been shown to have a good effect in alleviating nephrotic syndrome (NS) in clinical and in animal models of FSGS, but whether it can alleviate renal fibrosis in FSGS and its mechanism and targets are not clear. In this study, we explored the anti-fibrotic effect and the targets of the YSHS granule in an adriamycin (ADR)-induced FSGS model and found that the YSHS granule significantly improved the renal function of ADR-induced FSGS model mice and also significantly reduced the deposition of collagen fibers and the expression of mesenchymal cell markers FN, vimentin, and α-SMA in the glomeruli of ADR-induced FSGS mice, suggesting that the YSHS granule inhibited the fibrosis of sclerotic glomeruli. Subsequently, a network pharmacology-based approach was used to identify the potential targets of the YSHS granule for the alleviation of glomerulosclerosis in FSGS, and the results showed that the YSHS granule down-regulated the expressions of BMP2, GSTA1, GATS3, BST1, and S100A9 and up-regulated the expressions of TTR and GATM in ADR-induced FSGS model mice. We also proved that the YSHS granule inhibited the fibrosis in the glomeruli of ADR-induced FSGS model mice through the suppression of the BMP2/Smad signaling pathway.
10.3389/fphar.2022.917428
Ghrelin hormone a new molecular modulator between obesity and glomerular damage.
Molecular biology reports
The incidence of glomerular diseases is increasing worldwide due to increased prevalence of obesity which is a major risk factor for type-2 diabetes mellitus and cardiovascular disorders.Ghrelin, an orexigenic peptide hormone, has been implicated in obesity, and its impact on the pathology and function of the kidneys was found to be significant. Ghrelin known to regulate energy homeostasis and growth hormone release, has been shown to modulate critical signaling pathways involved in the health and survival of podocytes. These derangements directly affect glomerular function and manifest as impaired glomerular filtration barrier and leakage of albumin into urine. Although the pathological features of the above-mentioned disorders are different, they interestingly lead to similar clinical features of glomerular damage. The pathological events are majorly initiated by endocrine imbalance leading to abnormal activation of downstream signaling pathways involved in the development of glomerulosclerosis. In fact, obesity increases the risk of developing chronic kidney disease by altering the secretion of pro-inflammatory cytokines and adipokines, activating the renin-angiotensin-aldosterone system (RAAS), promoting lipotoxicity, oxidative stress and fibrosis within the kidneys. Whilst these bioregulators are well described, their direct involvement in renal homeostasis is still mostly elusive. This review summarized previous and recent evidence on the endocrine properties of ghrelin and perivascular adipose tissue involved in modulating kidney physiology.
10.1007/s11033-023-08866-8