Klotho: A Major Shareholder in Vascular Aging Enterprises.
Lim Kenneth,Halim Arvin,Lu Tzong-Shi,Ashworth Alan,Chong Irene
International journal of molecular sciences
Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched.
Role of Klotho in Chronic Calcineurin Inhibitor Nephropathy.
Luo Kang,Lim Sun Woo,Quan Yi,Cui Sheng,Shin Yoo Jin,Ko Eun Jeong,Chung Byung Ha,Yang Chul Woo
Oxidative medicine and cellular longevity
Calcineurin inhibitors (CNIs) are the most popular immunosuppressants in organ transplantation, but nephrotoxicity is a major concern. The common mechanism underlying chronic CNI nephropathy is oxidative stress, and the process of chronic CNI nephropathy is similar to that of aging. Current studies provide evidence that antiaging Klotho protein plays an important role in protecting against oxidative stress, and its signaling is a target for preventing oxidative stress-induced aging process. In this review, we focus on the association between Klotho and oxidative stress and the protective mechanism of action of Klotho against oxidative stress in chronic CNI nephropathy. In addition, we discuss the delivery strategy for Klotho in CNI-induced nephropathy.
Intracellular signaling of the aging suppressor protein Klotho.
Sopjani M,Rinnerthaler M,Kruja J,Dermaku-Sopjani M
Current molecular medicine
The Klotho protein deficiency is known to participate in premature aging. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity. Due to many reasons, the insulin/insulin-like growth factor-1 (IGF-1) has been considered as a key pathway in aging research. The Klotho gene is closely related to this pathway. The Klotho gene encodes a transmembrane protein that after cleavage is also found as a secreted protein. Importantly, its overexpression suppresses insulin/IGF-1 signaling and thus extends the lifespan. In addition, Klotho participates in the regulation of several other intracellular signaling pathways, including regulation of FGF23 signaling, cAMP, PKC, transforming growth factor-β (TGF-β), p53/p21, and Wnt signaling. The aim of this review is to summarize current literature that shows the involvement of Klotho in the regulation of several intracellular pathways. The results of our review clearly indicate that Klotho participates in several intracellular signaling pathways, and by regulating them, Klotho is involved in aging and longevity.
Klotho/FGF23 Axis in CKD.
Tsuchiya Ken,Nagano Nobuo,Nitta Kosaku
Contributions to nephrology
The sequential bone disorders, serum parameter abnormalities and vascular calcification that are associated with chronic kidney disease (CKD) have come to be generally known as CKD-mineral bone disorder (MBD). Klotho, a causative protein of aging, and fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic factor, have been reported to be involved in CKD-MBD, and their relationship to the pathophysiology of this disease is gradually being elucidated. Klotho functions as a cofactor of FGF receptors and has been reported to cause FGF23 action and specificity in the kidney. In addition, the presence of secreted Klotho in membrane protein fractions has been determined, and its specific actions are now garnering attention. FGF23, in cooperation with Klotho, inhibits phosphate reabsorption and vitamin D production at the kidney. Blood Klotho and FGF23 levels have been reported to increase beginning at the early stages of CKD, and these factors are receiving attention as new surrogate markers that are reported to be related to life expectancy. In this chapter, we summarize and outline the pathophysiology of Klotho and FGF23 in CKD-MBD as well as important points that are starting to influence clinical practice.
[FGF23 and Klotho protein--the role in the pathogenesis of hypertension].
Zając Magdalena,Rybi-Szumińska Agnieszka,Wasilewska Anna
Wiadomosci lekarskie (Warsaw, Poland : 1960)
Fibroblast growth factor 23 (FGF23) is a relatively new phosphatonin, which is produced mainly by bone cells. It is responsible for the regulation of calcium- phosphate homeostasis in the body. FGF23 is one of hormones with phosphaturic effect. It inhibits renal reabsorbtion of phosphate and increases its urinary excretion. Moreover, FGF23 decreases serum concentration of 1,25(OH)2D by inhibition of lα-hydroxylase and stimulation of 24-hydroxylase. The current knowledge on FGF23 and its cofactor-Klotho protein in disturbances of calcium-phosphate balance or in Chronic Kidney Disease is quite obvious. Still we need to know more about the influence of FGF23 on the cardiovascular system and its role in the pathogenesis of hypertension thus this will be the main aspect of our study.
Molecular basis of Klotho: from gene to function in aging.
Xu Yuechi,Sun Zhongjie
The discovery of the Klotho (KL) gene, which was originally identified as a putative aging-suppressor gene, has generated tremendous interest and has advanced understanding of the aging process. In mice, the overexpression of the KL gene extends the life span, whereas mutations to the KL gene shorten the life span. The human KL gene encodes the α-Klotho protein, which is a multifunctional protein that regulates the metabolism of phosphate, calcium, and vitamin D. α-Klotho also may function as a hormone, although the α-Klotho receptor(s) has not been found. Point mutations of the KL gene in humans are associated with hypertension and kidney disease, which suggests that α-Klotho may be essential to the maintenance of normal renal function. Three α-Klotho protein types with potentially different functions have been identified: a full-length transmembrane α-Klotho, a truncated soluble α-Klotho, and a secreted α-Klotho. Recent evidence suggests that α-Klotho suppresses the insulin and Wnt signaling pathways, inhibits oxidative stress, and regulates phosphatase and calcium absorption. In this review, we provide an update on recent advances in the understanding of the molecular, genetic, biochemical, and physiological properties of the KL gene. Specifically, this review focuses on the structure of the KL gene and the factors that regulate KL gene transcription, the key sites in the regulation of α-Klotho enzyme activity, the α-Klotho signaling pathways, and the molecular mechanisms that underlie α-Klotho function. This current understanding of the molecular biology of the α-Klotho protein may offer new insights into its function and role in aging.
Biological Role of Anti-aging Protein Klotho.
Kim Ji-Hee,Hwang Kyu-Hee,Park Kyu-Sang,Kong In Deok,Cha Seung-Kuy
Journal of lifestyle medicine
Klotho-deficient mice have accelerated aging phenotypes, whereas overexpression of Klotho in mice extends lifespan. Klotho is an anti-aging single-pass membrane protein predominantly produced in the kidney, with shedding of the amino-terminal extracellular domain into the systemic circulation. Circulating levels of soluble Klotho decrease with age, and the klotho gene is associated with increased risk of age-related diseases. The three forms of Klotho protein have distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors, functions as an obligatory co-receptor for FGF23, which is involved in aging and the development of chronic diseases via regulation of P i and vitamin D metabolism. Secreted Klotho functions as a humoral factor with pleiotropic activities including regulation of oxidative stress, growth factor signaling, and ion homeostasis. Secreted Klotho is also involved in organ protection. The intracellular form of Klotho suppresses inflammation-mediated cellular senescence and mineral metabolism. Herein we provide a brief overview of the structure and function and recent research about Klotho.
Significant roles of anti-aging protein klotho and fibroblast growth factor23 in cardiovascular disease.
Ding Hong-Ying,Ma Hou-Xun
Journal of geriatric cardiology : JGC
The klotho gene has been identified as an aging suppressor that encodes a protein involved in cardiovascular disease (CVD). The inactivation of the klotho gene causes serious systemic disorders resembling human aging, such as atherosclerosis, diffuse vascular calcification and shortened life span. Klotho has been demonstrated to ameliorate vascular endothelial dysfunction and delay vascular calcification. Furthermore, klotho gene polymorphisms in the human are associated with various cardiovascular events. Recent experiments show that klotho may reduce transient receptor potential canonical6 (TRPC6) channels, resulting in protecting the heart from hypertrophy and systolic dysfunction. Fibroblast growth factor23 (FGF23) is a bone-derived hormone that plays an important role in the regulation of phosphate and vitamin D metabolism. FGF23 accelerates urinary phosphate excretion and suppresses 1,25-dihydroxy vitaminD3 (1,25(OH)2D3) synthesis in the presence of FGF receptor1 (FGFR1) and its co-receptor klotho, principally in the kidney. The hormonal affects of circulating klotho protein and FGF23 on vascular and heart have contributed to an understanding of their roles in the pathophysiology of arterial stiffness and left ventricular hypertrophy. Klotho and FGF23 appear to play a critical role in the pathogenesis of vascular disease, and may represent a novel potential therapeutic strategy for clinical intervention.
[Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification in klotho deficient environment].
Hasegawa Tomoka,Yamamoto Tomomaya,Hongo Hiromi,Tsuboi Kanako,Amizuka Norio
Klotho deficient (kl/kl) mice exhibit Möncheberg's vascular calcification in the tunica media due to hyperphosphatemia and hypercalcemia by mediating the disrupted signaling of FGF23/klotho axis. Recent studies have hypothesized the mechanism of medial vascular calcification : Vascular smooth muscle cells acquired excessive intake of phosphate ions undergo a phenotypic differentiation into osteoblasts and induce biological calcification in the tunica media. It is useful to clarify the underlying cellular mechanism of vascular calcification for the development of the treatment and preventive medicine. This review will introduce the histological and ultrastructual findings on medial vascular calcification in kl/kl mice.
[Research Progress of Klotho].
Chang Jin-Rui,Sun Na,Nan Ying,Yu Wei,Qi Yong-Fen
Sheng li ke xue jin zhan [Progress in physiology]
Klotho, a newly identified anti-aging gene, can be regulated by many factors, such as calcitonin gene-related peptide, fibroblast growth factor 2 could up-regulate Klotho expression; whereas renin-angiotensin system, urinary toxins, inflammation and oxidative stress could reduce expression of Klotho. There are two forms of Klotho protein: membrane-bound Klotho and secreted Klotho. Existing studies showed that Klotho was involved in the development of many diseases, including vascular calcification, atherosclerosis, hypertension, kidney damage, hyperparathyroidism, diabetes and tumors. In this paper, the regulation of Klotho expression and its role in diseases are reviewed briefly.
Klotho-Dependent Cellular Transport Regulation.
Sopjani M,Dërmaku-Sopjani M
Vitamins and hormones
Klotho is a transmembrane protein that in humans is encoded by the hKL gene. This protein is known to have aging suppressor effects and is predominantly expressed in the distal convoluted tubule of the kidney, parathyroid glands, and choroid plexus of the brain. The Klotho protein exists in both full-length membrane form and a soluble secreted form, which exerts numerous distinct functions. The extracellular domain of Klotho can be enzymatically cleaved off and released into the systemic circulation where it functions as β-glucuronidase and a hormone. Soluble Klotho is a multifunction protein present in the biological fluids including blood, urine, and cerebrospinal fluid of mammals. Klotho deficiency leads to multiple organ failure accompanied by early appearance of multiple age-related disorders and early death, whereas overexpression of Klotho results in the opposite effects. Klotho, an enzyme and hormone, has been reported to participate in the regulation of cellular transport processes across the plasma membrane either indirectly through inhibiting calcitriol (1,25(OH)2D3) formation or other mechanism, or by directly affecting transporter proteins, including ion channels, cellular carriers, and Na(+)/K(+)-ATPase. Accordingly, Klotho protein serves as a powerful regulator of cellular transport across the plasma membrane. Importantly, Klotho-dependent cellular transport regulation implies stimulatory or inhibitory effects. Klotho has been shown to play a key role in the regulation of multiple calcium and potassium ion channels, and various cellular carriers including the Na(+)-coupled cotransporters such as NaPi-IIa, NaPi-IIb, EAAT3, and EAAT4, CreaT1 as well as Na(+)/K(+)-ATPase. These regulations are parts of the antiaging function of Klotho, which will be discussing throughout this chapter. Clearly, further experimental efforts are required to investigate the effect of Klotho on other transport proteins and underlying molecular mechanisms by which Klotho exerts its effect.
Klotho Prevents Translocation of NFκB.
Buendía P,Ramírez R,Aljama P,Carracedo J
Vitamins and hormones
Klotho protein is a β-glucuronidase capable of hydrolyzing steroid β-glucuronides. Two molecules are produced by the Klotho gene, a membrane bound form and a circulating form. This protein is recognized as an antiaging gene with pleiotropic functions. The activation of cellular systems is associated with the pathogenesis of several chronic and degenerative diseases associated with an inflammatory state. Inflammation is characterized by an activation of NFκB. Klotho suppresses nuclear factor NFκB activation and the subsequent transcription of proinflammatory genes. This review focuses on the current understanding of Klotho protein function and its relationship with NFκB regulation, emphasizing its potential involvement in the pathophysiologic process.
Klotho in cardiovascular disease: Current and future perspectives.
Donate-Correa Javier,Martín-Núñez Ernesto,Mora-Fernández Carmen,Muros-de-Fuentes Mercedes,Pérez-Delgado Nayra,Navarro-González Juan F
World journal of biological chemistry
Protein Klotho, beyond its role as a regulator of the phosphatemia, is also involved in the maintaining of the cardiovascular health, being associated its alterations with the development of cardiovascular damage and increased morbi-mortality. For all this, nowadays Klotho is the subject of a thorough research which is focused on uncover its intimate mechanisms of action, and in analyzing the utility of its modulation as a potential strategy with clinical applicability. Molecular mechanisms of Klotho are not well understood but an emerging research area links Klotho deficiency with vascular pathology. Changes in this protein have been associated with cardiovascular-related complications like inflammation, vascular calcification, and endothelial dysfunction. All this is particularly relevant if considering the recent discovery of Klotho expression in vascular tissue.
Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions.
Rubinek T,Modan-Moses D
Vitamins and hormones
The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is pivotal for many metabolic functions, including proper development and growth of bones, skeletal muscles, and adipose tissue. Defects in the axis' activity during childhood result in growth abnormalities, while increased secretion of GH from the pituitary results in acromegaly. In order to keep narrow physiologic concentration, GH and IGF-1 secretion and activity are tightly regulated by hypothalamic, pituitary, endocrine, paracrine, and autocrine factors. Klotho was first discovered as an aging-suppressor gene. Mice that do not express klotho die prematurely with multiple symptoms of aging, several of them are also characteristic of decreased GH/IGF-1 axis activity. Klotho is highly expressed in the brain, the kidney, and parathyroid and pituitary glands, but can also serve as a circulating hormone by its shedding, forming soluble klotho that can be detected in blood, cerebrospinal fluid, and urine. Several lines of evidence suggest an association between klotho levels and activity of the GH/IGF-1 axis: the GH-secreting cells in the anterior pituitary of klotho-deficient mice are hypotrophic; klotho levels are altered in subjects with pathologies of the GH/IGF-1 axis; and accumulating data indicate that klotho is a direct regulator of GH secretion. Thus, klotho seems to be a new player in the intricate regulation of the GH/IGF-1 axis.
The Role of Alpha-Klotho as a Universal Tumor Suppressor.
Rubinek T,Wolf I
Vitamins and hormones
The klotho gene is implicated in many physiological activities, among them aging, glucose metabolism, and phosphate and calcium metabolism. Many cellular activities of klotho were implicated in promoting these activities. Two of them, inhibition of the insulin-like growth factor-1 pathway and of the Wnt signaling pathway, are also major pathways associated with cancer development and progression. These discoveries prompted a surge of research aiming to elucidate the role of klotho in cancer. Studies show that klotho is universally silenced in a wide array of malignancies, including breast, pancreatic, ovarian, lung, colorectal, and melanoma, and that klotho's expression can serve as an invaluable prognostic marker. Epigenetic mechanisms, ie, promoter hypermethylation and histone deacetylation, are mainly associated with klotho's silencing; however, different micro-RNAs were also demonstrated to be involved in the process. The activity of klotho on cancer cells growth was also widely investigated, and accumulating data suggest that klotho forced expression or treatment with the soluble protein can inhibit cancer development and progression. Moreover, studies now aim to reveal the specific region in klotho protein that underlies this anticancer activity in order to develop efficient and safe klotho-based medications.
Deficiency of Soluble α-Klotho as an Independent Cause of Uremic Cardiomyopathy.
Xie J,Wu Y-L,Huang C-L
Vitamins and hormones
Cardiovascular disease (CVD) is the major cause of mortality for patients with chronic kidney disease (CKD). Cardiac hypertrophy, occurring in up to 95% patients with CKD (also known as uremic cardiomyopathy), increases their risk for cardiovascular death. Many CKD-specific risk factors of uremic cardiomyopathy have been recognized, such as secondary hyperparathyroidism, indoxyl sulfate (IS)/p-cresyl, and vitamin D deficiency. However, several randomized controlled trials have recently shown that these risk factors have little impact on the mortality of CVD. Klotho is a type 1 membrane protein predominantly produced in the kidney, and CKD is known to be a Klotho-deficient state. Because of its important role in FGF23 and phosphate metabolism, Klotho is believed to affect cardiac growth and function indirectly through FGF23 and phosphate. Recent studies showed that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by inhibiting TRPC6 channel-mediated abnormal Ca(2+) signaling in the heart, and the decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate. These new evidence suggested that Klotho is an independent contributing factor for uremic cardiomyopathy and a possible new target for treatment of this disease.
The Role of Klotho Protein in Chronic Kidney Disease: Studies in Animals and Humans.
Gołembiewska Edyta,Stępniewska Joanna,Kabat-Koperska Joanna,Kędzierska Karolina,Domański Maciej,Ciechanowski Kazimierz
Current protein & peptide science
The identification of Klotho gene was a major discovery as the gene encodes a protein regulating multiple functions. A defect in Klotho gene expression in mice results in a phenotype of premature aging including shortened life span, growth retardation, hypogonadism, skin and muscle atrophies, vascular calcification, cognition impairment, motor neuron degeneration and others. This phenotype is associated with phosphate balance disorders and underlines the major function of Klotho in mineral metabolism. As another 2 related paralogs were discovered (beta-Klotho, which is involved in bile acid and energy metabolism, and gamma-Klotho, with a yet to be defined function), this led to the revised naming of Klotho as alpha-Klotho. Two forms of alpha-Klotho protein have been reported: a membrane-bound and a soluble one. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for the FGF-23 phosphatonin in distal tubules. The soluble form of Klotho seems to function as a humoral factor and regulates glycoproteins on the cell surface including ion channels and growth factors. There is data suggesting that soluble Klotho exerts phosphaturic effects independently of FGF-23. Circulating soluble Klotho is produced either by proteolytic cleavage of the extracellular domain of the transmembrane form by two membrane-anchored proteases (ADAM10 and ADAM17) or by alternative mRNA splicing. In animal models Klotho has been shown to exert pleiotropic actions, including cytoprotection, anti-oxidation, anti-apoptosis, protection of vasculature, promotion of angiogenesis and vascularization, inhibition of fibrogenesis and preservation of stem cells. The exact diagnostic and therapeutic role of Klotho in humans is not fully known yet. The article presents the role of Klotho in physiology and different stages of chronic kidney disease (CKD).
Bone mineral disorder in chronic kidney disease: Klotho and FGF23; cardiovascular implications.
Salanova Villanueva Laura,Sánchez González Carmen,Sánchez Tomero José Antonio,Aguilera Abelardo,Ortega Junco Esther
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia
Cardiovascular factors are one of the main causes of morbidity and mortality in patients with chronic kidney disease. Bone mineral metabolism disorders and inflammation are pathological conditions that involve increased cardiovascular risk in chronic kidney disease. The cardiovascular risk involvement of bone mineral metabolism classical biochemical parameters such as phosphorus, calcium, vitamin D and PTH is well known. The newest markers, FGF23 and klotho, could also be implicated in cardiovascular disease.
The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy.
Grabner Alexander,Faul Christian
Current opinion in nephrology and hypertension
PURPOSE OF REVIEW:In chronic kidney disease (CKD), multiple factors contribute to the development of cardiac hypertrophy by directly targeting the heart or indirectly by inducing systemic changes such as hypertension, anemia, and inflammation. Furthermore, disturbances in phosphate metabolism have been identified as nonclassical risk factors for cardiovascular mortality in these patients. With declining kidney function, the physiologic regulators of phosphate homeostasis undergo changes in their activity as well as their circulating levels, thus potentially contributing to cardiac hypertrophy once they are out of balance. Recently, two of these phosphate regulators, fibroblast growth factor 23 (FGF23) and Klotho, have been shown to affect cardiac remodeling, thereby unveiling a novel pathomechanism of cardiac hypertrophy in CKD. Here we discuss the potential direct versus indirect effects of FGF23 and the soluble form of Klotho on the heart, and their crosstalk in the regulation of cardiac hypertrophy. RECENT FINDINGS:In models of CKD, FGF23 can directly target cardiac myocytes via FGF receptor 4 and induce cardiac hypertrophy in a blood pressure-independent manner. Soluble Klotho may directly target the heart via an unknown receptor thereby protecting the myocardium from pathologic stress stimuli that are associated with CKD, such as uremic toxins or FGF23. SUMMARY:Elevated serum levels of FGF23 and reduced serum levels of soluble Klotho contribute to uremic cardiomyopathy in a synergistic manner.
The Longevity Hormone Klotho is a New Player in the Interacion of the Growth Hormone/Insulin-Like Growth Factor 1 Axis.
Rubinek Tami,Wolf Ido,Modan-Moses Dalit
Pediatric endocrinology reviews : PER
Klotho was first discovered as an aging-suppressor gene. Mice that do not express klotho die prematurely with multiple symptoms of aging, several of which are also characteristic of decreased GH/IGF-1 axis activity. Klotho is highly expressed in the brain, the kidney, and parathyroid and pituitary glands, but can also serve as a circulating hormone by its shedding, forming soluble klotho (sKlotho) that can be detected in blood, cerebrospinal fluid and urine. Several lines of evidence suggest an association between klotho levels and activity of the GH/IHG-1 axis: The GH-secreting cells in the anterior pituitary of klotho-deficient mice are hypotrophic; klotho levels are altered in subjects with pathologies of the GH/IGF-1 axis; and accumulating data indicate that klotho is a direct regulator of GH secretion. Thus, klotho seems to be a new player in the intricate regulation of the GH/IGF-1 axis.
Update on FGF23 and Klotho signaling.
Erben Reinhold G
Molecular and cellular endocrinology
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption and vitamin D hormone production in the kidney. Klotho was originally discovered as an anti-aging factor, but the functional role of Klotho is still a controversial issue. Three major functions have been proposed, a hormonal function of soluble Klotho, an enzymatic function as glycosidase, and the function as an obligatory co-receptor for FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23 and Klotho signaling in the kidney, in the parathyroid gland, in the cardiovascular system, in bone, and in the central nervous system. During recent years, major new functions of FGF23 and Klotho have been discovered in these organ systems. Based on these novel findings, FGF23 has emerged as a pleiotropic endocrine and auto-/paracrine factor influencing not only mineral metabolism but also cardiovascular function.
The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis.
Hormone molecular biology and clinical investigation
The function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders.
Klotho, the Holy Grail of the kidney: from salt sensitivity to chronic kidney disease.
Kalaitzidis Rigas G,Duni Anila,Siamopoulos Kostas C
International urology and nephrology
The Klotho gene displays an extremely shortened life span with loss of function missense mutations leading to premature multiple organ failure, thus resembling human premature aging syndromes. The transmembrane form of Klotho protein functions as an obligatory co-receptor for FGF23. Klotho and FGF23 are crucial components for the regulation of vitamin D metabolism and subsequently blood phosphate levels. The secreted Klotho protein has multiple regulatory functions, including effects on electrolyte homeostasis, on growth factor pathways as well as on oxidative stress, which are currently the object of extensive research. Klotho protein deficiency is observed in many experimental and clinical disease models. Genetic polymorphisms such as the G-395A polymorphism in the promoter region of the Klotho gene have been associated with the development of essential hypertension. The kidneys are the primary site of Klotho production, and renal Klotho is decreased in CKD, followed by a reduction in plasma Klotho. Klotho deficiency has been both associated with progression of CKD as well as with its cardinal systemic manifestations, including cardiovascular disease. Thus, Klotho has been suggested both as a risk biomarker for early detection of CKD and additionally as a potential therapeutic tool in the future.
[Klotho not only antiageing protein].
Sosnowski Bartosz,Bachórzewska-Gajewska Hanna,Dobrzycki Slawomir,Malyszko Jolanta
Klotho, the gene encoding theantiaging protein, was discovered in1997 and named after a Greek Goddeswho spun the thread of life. Numerousexperiments on mice confirmed thatdestruction of the klotho gene or lossof klotho function leads to an acceleratedaging and premature death.In addition to shortened life span,klotho-deficient mice demonstratedchanges in functioning of multipleorgans, ectopic calcification, enhanceddevelopment of arteriosclerosis,osteoporosis and atrophy of skin. Incontrast, overexpression of a gene inmice inhibited aging and prolongedsurvival. The multisystemic phenotypeinduced by Klotho deficiency indicatesthat Klotho works on a variety oforgans. Klotho is highly expressedin the kidney, brain, and to a lesserextent in other organs. Protein Klothoexists in two forms: membrane andsecreted which play different functions.Membrane Klotho function asan obligate co-receptor required forsignaling for the phosphaturic factorFGF23, regulates calcium-phosphatehomeostasis through renal ion transportin addition to modulation of PTHand 1,25(OH)2D3. Soluble klotho functionsas a humoral factor and regulatesthe activity of several ion channels andtransporters. The secreted Klotho canalso inhibit oxydative stres and theinsulin and insulin-like growth factor 1(IGF-1) pathways. The discovery of theprotein klotho led to the identificationof new axes connecting endocrinedisturbances in the homeostasis ofthe calcium-phosphate to the aging ofthe organism. Klotho deficiency maynot only be a trigger for acceleratedaging but also in development of age--associated diseases, including hypertension,osteoporosis, cardiovasculardisease, and CKD. Conceivably, betterunderstanding of Klotho protein mightprovide a novel treatment strategy foraging and age-associated diseases.
Potential application of klotho in human chronic kidney disease.
Neyra Javier A,Hu Ming Chang
The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.
The effects of aerobic and anaerobic exercises on circulating soluble-Klotho and IGF-I in young and elderly adults and in CAD patients.
Saghiv Moran S,Sira D Ben,Goldhammer E,Sagiv M
Journal of circulating biomarkers
Different studies support the notion that chronic aerobic exercises training can influence the circulating levels of soluble-Klotho (s-Klotho) and insulin-like growth factor 1 (IGF-I). The effects of s-Klotho include improving the quality of life, alleviating the negative impact of age on the body's work capacity, and possibly increasing longevity. This review provides an overview of the latest findings in this field of research in humans. The different modes of dynamic exercise and their impact on circulating levels of s-Klotho and IGF-I in young adult athletes, untrained young adults, trained healthy older adults, untrained healthy older adults, and coronary artery disease (CAD) patients are reviewed and discussed. Together these findings suggest that long-lasting (chronic) aerobic exercise training is probably one of the antiaging factors that counteract the aging and CAD process by increasing the circulating s-Klotho and lowering the IGF-I levels. However, following anaerobic exercise training the opposite occurs. The exact metabolic and physiological pathways involved in the activity of these well-trained young and master sportsmen should be further studied and elucidated. The purpose of this review was to provide a clarification regarding the roles of s-Klotho and intensities and durations of different exercise on human health.
Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies.
Mencke Rik,Olauson Hannes,Hillebrands Jan-Luuk
Advanced drug delivery reviews
Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFβ1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFβ1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies.
New Insights into the Mechanism of Action of Soluble Klotho.
Dalton George D,Xie Jian,An Sung-Wan,Huang Chou-Long
Frontiers in endocrinology
The gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl's mechanism of action as a "hormone" has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl's mechanism of action, the mechanistic basis of sKl's protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling.
Klotho-FGF23, Cardiovascular Disease, and Vascular Calcification: Black or White?
Cianciolo Giuseppe,Galassi Andrea,Capelli Irene,Schillaci Roberto,La Manna Gaetano,Cozzolino Mario
Current vascular pharmacology
BACKGROUND:Patients affected by Chronic Kidney Disease and Mineral Bone Disorder (CKD-MBD) have a high risk of cardiovascular (CV) mortality that is poorly explained by traditional risk factors. The newest medical treatments for CKD-MBD have been associated with encouraging, but still inconsistent, improvement in CV disease complications and patient survival. A better understanding of the biomarkers and mechanisms of left ventricular hypertrophy (LVH), atherosclerosis, and vascular calcification (VC) may help with diagnosis and treatment of the organ damage that occurs secondary to CKD-MBD, thus improving survival. Recent insights about fibroblast growth factor-23 (FGF23) and its co-receptor, Klotho, have led to marked advancement in interpreting data on vascular aging and CKDMBD. CONCLUSION:This review will discuss the current experimental and clinical evidence regarding FGF23 and Klotho, with a particular focus on their roles in LVH, atherosclerosis, and VC.
Klotho protein function among patients with type 1 diabetes.
Flotyńska Justyna,Uruska Aleksandra,Araszkiewicz Aleksandra,Zozulińska-Ziółkiewicz Dorota
The fibroblast growth factor 23 (FGF23) and Klotho system play a very important role in the regulation of the human body metabolism. On the one hand, they promote longevity, and on the other hand they promote insulin resistance. Nowadays, accelerated aging in diabetes as the main consequence of chronic complications of the disease is postulated. Signalling pathways induced by insulin, insulin-like growth factor (IGF-1), and their homologues play an important role in controlling the aging process. Because FGF23/Klotho system affects glucose metabolism and gene expression of antioxidant enzymes, changes in its concentration may be a marker of chronic complications of diabetes or a treatment option. Despite huge improvements in the treatment of diabetes, its chronic complications remain an important clinical problem. An interesting issue is the relationship between the concentration of FGF23/Klotho and management of the disease, duration, insulin resistance, and development of complications in type 1 diabetes.
Changes in expression of klotho affect physiological processes, diseases, and cancer.
Xuan Nguyen Thi,Hai Nong Van
Iranian journal of basic medical sciences
encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion. Accordingly, mutant mice display multiple aging-like phenotypes, which are ameliorated by overexpression of KL. Therefore, KL is an important contributor to lifespan. KL is further identified as a regulator of calcium (Ca) channel-dependent cell physiological processes. KL has been also shown to induce cancer cell apoptosis, thus, it is considered as a potential tumor suppressor. Our recent studies have indicated that KL modulates an influx of Ca from the extracellular space, leading to a change in CCL21-dependent migration in dendritic cells (DCs). Interestingly, the regulation of the expression of KL was mediated through a phosphoinositide 3-kinase (PI3K) pathway in DCs. Moreover, downregulating of KL expression by using siRNA knockdown technique, we observed that the expression of Ca channels including Orai3, but not Orai1, Orai2, TRPV5 and TRPV6 was significantly reduced in -silenced as compared to control BMDCs. Clearly, additional research is required to define the role of KL in the regulation of organismic and cellular functions through the PI3K signaling and the expression of the Ca channels.
PTH, vitamin D, and the FGF-23-klotho axis and heart: Going beyond the confines of nephrology.
Navarro-García José Alberto,Fernández-Velasco María,Delgado Carmen,Delgado Juan F,Kuro-O Makoto,Ruilope Luis M,Ruiz-Hurtado Gema
European journal of clinical investigation
BACKGROUND:Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart. AIM:The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting. RESULTS:Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF-23-klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF-23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation. CONCLUSIONS:Among all mineral components, an increase in systemic FGF-23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF-23, especially those related to cardiomyocyte function, remain to be discovered.
Therapeutic Interference With Vascular Calcification-Lessons From Klotho-Hypomorphic Mice and Beyond.
Lang Florian,Leibrock Christina,Pelzl Lisann,Gawaz Meinrad,Pieske Burkert,Alesutan Ioana,Voelkl Jakob
Frontiers in endocrinology
Medial vascular calcification, a major pathophysiological process associated with cardiovascular disease and mortality, involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). In chronic kidney disease (CKD), osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification is mainly driven by hyperphosphatemia, resulting from impaired elimination of phosphate by the diseased kidneys. Hyperphosphatemia with subsequent vascular calcification is a hallmark of klotho-hypomorphic mice, which are characterized by rapid development of multiple age-related disorders and early death. In those animals, hyperphosphatemia results from unrestrained formation of 1,25(OH)D with subsequent retention of calcium and phosphate. Analysis of klotho-hypomorphic mice and mice with vitamin D overload uncovered several pathophysiological mechanisms participating in the orchestration of vascular calcification and several therapeutic opportunities to delay or even halt vascular calcification. The present brief review addresses the beneficial effects of bicarbonate, carbonic anhydrase inhibition, magnesium supplementation, mineralocorticoid receptor (MR) blockage, and ammonium salts. The case is made that bicarbonate is mainly effective by decreasing intestinal phosphate absorption, and that carbonic anhydrase inhibition leads to metabolic acidosis, which counteracts calcium-phosphate precipitation and VSMC transdifferentiation. Magnesium supplementation, MR blockage and ammonium salts are mainly effective by interference with osteo-/chondrogenic signaling in VSMCs. It should be pointed out that the, by far, most efficient substances are ammonium salts, which may virtually prevent vascular calcification. Future research will probably uncover further therapeutic options and, most importantly, reveal whether these observations in mice can be translated into treatment of patients suffering from vascular calcification, such as patients with CKD.
Ischemic acute kidney injury and klotho in renal transplantation.
Panah Fatemeh,Ghorbanihaghjo Amir,Argani Hassan,Asadi Zarmehri Maryam,Nazari Soltan Ahmad Saeed
Post-transplant ischemic acute kidney injury (AKI), secondary to ischemia reperfusion injury (IRI), is a major problem influencing on the short and long term graft and patient survival. Many molecular and cellular modifications are observed during IRI, for example, tissue damage result production of reactive oxygen species (ROS), cytokines, chemokines, and leukocytes recruitment which are activated by NF-κB (nuclear factor kappa B) signaling pathway. Therefore, inhibiting these processes can significantly protect renal parenchyma from tissue damage. Klotho protein, mainly produced in distal convoluted tubules (DCT), is an anti-senescence protein. There is increasing evidence to confirm a relationship between Klotho levels and renal allograft function. Many studies have also demonstrated that expression of the Klotho gene would be down regulated with IRI, so it will be used as an early biomarker for acute kidney injury after renal transplantation. Other studies suggest that Klotho may have a renoprotective effect for attenuating of kidney injury. In this review, we will discuss pathophysiology of IRI-induced acute kidney injury and its relation with klotho level in renal transplantation procedure.
FGF23 Actions on Target Tissues-With and Without Klotho.
Richter Beatrice,Faul Christian
Frontiers in endocrinology
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in "classic" klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23's potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho.
Molecular Mechanisms Underlying Accelerated Aging by Defects in the FGF23-Klotho System.
International journal of nephrology
The basic research of aging has been primarily focused on elucidating mechanisms of aging and longevity that are evolutionarily conserved from yeasts to primates. Such efforts have culminated in the notion that (1) senescence at the cellular level is associated with aging at the organismal level and that (2) calorie restriction and growth suppression decelerate aging. However, these important findings in the basic research have not necessarily been linked to improvement of daily medical practice in the aging society. It has become increasingly important to investigate mechanisms of aging unique to mammals or humans and apply the research fruits for the treatment of major age-related disorders to extend the health span. Seminal studies on the mouse, a mutant exhibiting a premature aging syndrome, have identified phosphate as a proaging factor in mammals. In this review, mechanisms of phosphate-induced premature aging and potential therapeutic targets will be discussed, which may be directly applicable for developing novel strategies for the treatment of chronic kidney disease and its complications.
Klotho, the Key to Healthy Brain Aging?
Vo Hai T,Laszczyk Ann M,King Gwendalyn D
Brain plasticity (Amsterdam, Netherlands)
Brain expression of klotho was first described with the initial discovery of the klotho gene. The prominent age-regulating effects of klotho are attributed to regulation of ion homeostasis through klotho function in the kidney. However, recent advances identified brain functions and cell populations, including adult hippocampal neural progenitors, which require klotho. As well, both human correlational studies and mouse models of disease show that klotho is protective against multiple neurological and psychological disorders. This review focuses on current knowledge as to how the klotho protein effects the brain.
Correlation between Soluble -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis.
Wang Qinglian,Su Wenyan,Shen Zhenwei,Wang Rong
BioMed research international
Objective:Over decades, numerous inconsistent studies are reported on the relationship between soluble -Klotho and renal function in patients with chronic kidney disease (CKD). This study aims to perform a meta-analysis to figure out the correlations between soluble -Klotho and renal function in patients with CKD. Materials and Methods:We searched medical and scientific literature databases, PubMed and EMBASE (from the inception to October 2017), for publications that reported studies on associations between soluble -Klotho and renal function in patients with CKD. Only publications in English were extracted. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Publication bias was tested, and sensitivity and subgroup analyses were performed to investigate potential heterogeneity. Results:Of 611 studies, 9 publications with 1457 patients were included into the analysis. The following data were extracted from the literature: first author, year of publication, research region, research index, sample size, average age and Pearson or Spearman correlation coefficient, study design, the Klotho/FGF23 assays utilized, full length, or the C-terminal fragment of FGF23. The pooled r between -Klotho and estimated glomerular filtration rate (eGFR), FGF-23 were 0.35 (95%CI, 0.23~0.46, and P<0.05), -0.10 (95%CI, -0.19~-0.01, and P<0.05) with remarkable significance, indicating moderate heterogeneity. There was no significant heterogeneity between subgroups in analyses of -Klotho and eGFR stratified by research region, mean age, and eGFR, but heterogeneity exists in analyses of -Klotho and FGF-23 stratified by research region. There was no significant correlation between a-klotho and Ca and PTH and PHOS. There was no evidence of publication bias with Egger's test (p=0.360) or with Begg's test (p=0.902) and the distribution of funnel plots was symmetrical in all of our analysis. Conclusions:There exists a significant positive correlation between soluble -Klotho and eGFR in patients with CKD. Also, a significant negative correlation between -Klotho and FGF23 levels is proven. This raises hope to employ Klotho and FGF23 as early biomarkers of CKD. However, further large prospective follow-up researches are needed to validate this hypothesis and to explore whether maintaining or elevating the Klotho level could improve renal function and complications in CKD patients.
Role of Klotho in bone and implication for CKD.
Komaba Hirotaka,Lanske Beate
Current opinion in nephrology and hypertension
PURPOSE OF REVIEW:Klotho is a transmembrane protein that acts as a co-receptor for fibroblast growth factor 23 (FGF23). Recent investigations have discovered the presence of Klotho in bone-forming osteoblasts and osteocytes. This review summarizes emerging literature on the roles of bone Klotho in mineral and bone metabolism and discusses their possible involvement in renal osteodystrophy. RECENT FINDINGS:Mouse genetic studies have demonstrated that loss of Klotho in osteocytes leads to increased bone formation and bone volume. The identification of Klotho expression in bone cells pointed to the possibility that the bone is another target organ for FGF23, providing a new basis for extending the interpretation of previous research findings. Along with this paradigm shift, recent investigations uncovered the autocrine/paracrine functions of FGF23 as a critical regulator of its own production and the Wnt-mediated bone formation. These effects may, however, be offset by down-regulation of bone Klotho in renal failure. SUMMARY:Klotho expressed in bone cells has functional roles in controlling bone formation and regulating FGF23 production. Additional studies are needed to translate these findings into the development of new therapeutic approaches for the treatment of bone fragility in patients with renal osteodystrophy and other bone diseases.
FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism.
Calcified tissue international
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism.
Klotho protein in neurodegenerative disorders.
Torbus-Paluszczak Magdalena,Bartman Wojciech,Adamczyk-Sowa Monika
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
The Klotho protein is a recently discovered protein and its overexpression is associated with life extension. Klotho deficiency or silencing of the Klotho gene in mice leads to an accelerated aging and short life, whereas overexpression of Klotho in mice extends lifespan. Klotho participates in many metabolic pathways and is highly expressed in the kidneys, the choroid plexus and neurons. It plays a key role in the calcium-phosphate metabolism, remyelination, and cognitive processes. The present paper is a short review of the literature on the role of Klotho in neurodegenerative disorders, with special attention paid to multiple sclerosis. The neuroprotective function of Klotho is also reported. It is also important to consider potential clinical applications of Klotho that might be useful in the treatment of many diseases.
[Research update of Klotho in kidney injury and repair].
Dai Hou-Yong,Yang Bin
Sheng li xue bao : [Acta physiologica Sinica]
Klotho is highly expressed in the kidney, while soluble Klotho is detectable in the blood, urine, and cerebrospinal fluid, and has multiple hormone-like functions. The role of Klotho in kidney injury has attracted more and more attentions from researchers. Emerging evidence revealed that the transient deficiency of Klotho is an early event of acute kidney injury (AKI), whereas, in chronic kidney disease, this deficiency is sustained not only in the kidney, but also in other organ systems. Therefore, Klotho could be a potential biomarker for early diagnosis of AKI, as well as for its progression to chronic kidney disease. Moreover, Klotho might have therapeutic value to renal injury. Nevertheless, there are only few studies on the involvement of Klotho in post AKI repair. This review focused on the role of Klotho in not only kidney injury, but also its repair, in particular the relationship between Klotho and cell fate (autophagy/apoptosis/necrosis), repair/regeneration, Wnt/β-catenin and erythropoietin receptor, one of the Klotho effectors.
The role of klotho in chronic kidney disease.
Zou Di,Wu Wen,He Yan,Ma Sichao,Gao Ji
Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.
The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases.
Olejnik Agnieszka,Franczak Aleksandra,Krzywonos-Zawadzka Anna,Kałużna-Oleksy Marta,Bil-Lula Iwona
BioMed research international
Klotho is a membrane-bound or soluble antiaging protein, whose protective activity is essential for a proper function of many organs. In 1997, an accidental insertion of a transgene led to creation of transgenic mice with several age-related disorders. In Klotho-deficient mice, the inherited phenotypes closely resemble human aging, while in an animal model of Klotho overexpression, the lifespan is extended. Klotho protein is detected mainly in the kidneys and brain. It is a coreceptor for fibroblast growth factor and hence is involved in maintaining endocrine system homeostasis. Furthermore, an inhibition of insulin/insulin-like growth factor-1 signaling pathway by Klotho regulates oxidative stress and reduces cell death. The association between serum Klotho and the classic risk factors, as well as the clinical history of cardiovascular disease, was also shown. There are a lot of evidences that Klotho deficiency correlates with the occurrence and development of coronary artery disease, atherosclerosis, myocardial infarction, and left ventricular hypertrophy. Therefore, an involvement of Klotho in the signaling pathways and in regulation of a proper cell metabolism could be a crucial factor in the cardiac and vascular protection. It is also well established that Klotho protein enhances the antioxidative response via augmented production of superoxide dismutase and reduced generation of reactive oxygen species. Recent studies have proven an expression of Klotho in cardiomyocytes and its increased expression in stress-related heart injury. Thus, the antioxidative and antiapoptotic activity of Klotho could be considered as the novel protective factor in cardiovascular disease and heart injury.
Implications of Fibroblast growth factor/Klotho system in glucose metabolism and diabetes.
Donate-Correa Javier,Martín-Núñez Ernesto,Delgado Nayra Pérez,de Fuentes Mercedes Muros,Arduan Alberto Ortiz,Mora-Fernández Carmen,Navarro González Juan F
Cytokine & growth factor reviews
Diabetes mellitus, especially type 2 diabetes, remains the dominant metabolic disease worldwide, with an expected increase in prevalence of over 50% in the next 20 years. Our knowledge about the pathophysiology of type 2 diabetes continues to be incomplete, with unmet medical need for new therapies. The characterization of the fibroblast growth factor (FGF) family and the discovery of endocrine FGFs provided new information on the mechanisms of regulation and homeostasis of carbohydrate metabolism. More specifically, FGF19 and FGF21 signaling pathways have been linked to different glucose metabolic processes, including hepatic glucose synthesis, glycogen synthesis, glucose uptake, and insulin sensitivity, among others, and these molecules have been further related to the pathophysiology of diabetes mellitus. In-depth comprehension of these growth factors may bring to light new potential therapeutic targets for the treatment of diabetes mellitus.
Klotho as a Therapeutic Target during the Development of Renal Fibrosis.
Doi Shigehiro,Masaki Takao
Contributions to nephrology
Systemic symptoms such as the ectopic calcification, atrophy of skin and muscle, and impaired sexual function observed in chronic kidney diseases (CKD) have been reported to coincide with those observed in geriatric symptoms. Regarding the kidney, clinical/pathological characteristics in CKD patients also coincide with those in the aging kidney. These findings suggest common mechanisms in the development of both CKD and aging. Our investigation of aging factors associated with renal fibrosis in IgA nephropathy patients revealed a significant correlation between accumulation of cells with an arrested cell cycle and decreased expression of Klotho protein. Because cell cycle arrest has a protective effect on organs in the acute phase, the proposed therapeutic target against the aging process is to maintain expression of Klotho protein. In addition, it is recognized that TGF-β1 plays a central role in the development of renal fibrosis. However, TGF-β1 has also been reported to decrease expression of Klotho protein. In this report, we provide an interpretation of our new treatment strategy which involves controlling histone methylation.
The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology.
Mencke Rik,Hillebrands Jan-Luuk,
Ageing research reviews
Klotho is an anti-ageing protein that functions in many pathways that govern ageing, like regulation of phosphate homeostasis, insulin signaling, and Wnt signaling. Klotho expression levels and levels in blood decline during ageing. The vascular phenotype of Klotho deficiency features medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension, and impaired angiogenesis and vasculogenesis, with characteristics similar to aged human arteries. Klotho-deficient phenotypes can be prevented and rescued by Klotho gene expression or protein supplementation. High phosphate levels are likely to be directly pathogenic and are a prerequisite for medial calcification, but more important determinants are pathways that regulate cellular senescence, suggesting that deficiency of Klotho renders cells susceptible to phosphate toxicity. Overexpression of Klotho is shown to ameliorate medial calcification, endothelial dysfunction, and hypertension. Endogenous vascular Klotho expression is a controversial subject and, currently, no compelling evidence exists that supports the existence of vascular membrane-bound Klotho expression, as expressed in kidney. In vitro, Klotho has been shown to decrease oxidative stress and apoptosis in both SMCs and ECs, to reduce SMC calcification, to maintain the contractile SMC phenotype, and to prevent μ-calpain overactivation in ECs. Klotho has many protective effects with regard to the vasculature and constitutes a very promising therapeutic target. The purpose of this review is to explore the etiology of the vascular phenotype of Klotho deficiency and the therapeutic potential of Klotho in vascular disease.
FGF23-Klotho signaling axis in the kidney.
Erben Reinhold G,Andrukhova Olena
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na/H exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease.
Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho.
Yamada Shunsuke,Giachelli Cecilia M
Vascular calcification (VC) is highly prevalent in aging, diabetes mellitus, and chronic kidney disease (CKD). VC is a strong predictor of cardiovascular morbidity and mortality in the CKD population. Complex pathological mechanisms are involved in the development of VC, including osteochondrogenic differentiation and apoptosis of vascular smooth muscle cells, instability and release of extracellular vesicles loaded calcium and phosphate, and elastin degradation. Elevated serum phosphate is a late manifestation of CKD, and has been shown to accelerate mineral deposition in both the vessel wall and heart valves. α-Klotho and fibroblast growth factor 23 (FGF23) are emerging factors in CKD-mineral and bone disorder (CKD-MBD) and are thought to be involved in the pathogenesis of uremic VC. There are discordant reports regarding the biomedical effects of FGF23 on VC. In contrast, mounting evidence supports a well-supported protective role for α-Klotho on VC. Further studies are warranted to elucidate potential roles of FGF23 and α-Klotho in VC and to determine where and how they are synthesized in normal and disease conditions. A thorough systemic evaluation of the biomedical interplay of phosphate, FGF23, and α-Klotho may potentially lead to new therapeutic options for patients with CKD-MBD.
Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease.
Lu Xiang,Hu Ming Chang
Kidney diseases (Basel, Switzerland)
BACKGROUND:Membrane αKlotho (hereinafter called Klotho) is highly expressed in the kidney and functions as a coreceptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in the maintenance of mineral homeostasis. The extracellular domain of transmembrane Klotho can be cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho does not only weakly activate FGFRs to transduce the FGF23 signaling pathway, but also functions as an enzyme and hormonal substance to play a variety of biological functions. FGF23 exerts its biological effects through activation of FGFRs in a Klotho-dependent manner. However, extremely high FGF23 can exert its pathological action in a Klotho-independent manner. SUMMARY:The decline in serum and urinary Klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease (CKD) functions as an early biomarker for kidney dysfunction and can also serve as a predictor for risk of cardiovascular disease (CVD) and mortality in both CKD patients and the general population. Moreover, Klotho deficiency is a pathogenic factor for CKD progression and CVD. FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment. KEY MESSAGE:Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics.
Novel functions of circulating Klotho.
Hum Julia M,O'Bryan Linda,Smith Rosamund C,White Kenneth E
A significant portion of the key biological functions of αKlotho (αKL) and its cognate ligand Fibroblast growth factor-23 (FGF23) have been revealed through the study of rare diseases of mineral metabolism. These findings have far reaching implications for common disorders such as chronic kidney disease-mineral bone disorder (CKD-MBD). αKL's predominant effect on mineral homeostasis is through its actions in the kidney as a co-receptor for FGF23, however emerging data has shed light on its capacity to act as a circulating factor through the cleavage of the transmembrane form of αKL ('mKL') to produce 'cleaved KL' or 'cKL'. This review summarizes new findings from studies using extended delivery of cKL to mouse models with phenotypes reflecting those arising in CKD-MBD.