-
[show abstract]
[hide abstract]
ABSTRACT: Klotho is a single-pass transmembrane protein highly expressed in the kidney. Membrane Klotho protein acts as a co-receptor for fibroblast growth factor-23. Its extracellular domain is shed from the cell surface and functions as an endocrine substance that exerts multiple renal and extrarenal functions. An exhaustive review is beyond the scope and length of this article; thus, only effects with pertinence to mineral metabolism and renoprotection are highlighted here. Klotho participates in mineral homeostasis via interplay with other calciophosphoregulatory hormones (parathyroid hormone, fibroblast growth factor-23, and 1,25-[OH] vitamin D) in kidney, bone, intestine, and parathyroid gland. Klotho also may be involved in acute and chronic kidney disease development and progression. Acute kidney injury is a temporary and reversible state of Klotho deficiency and chronic kidney disease is a sustained state of systemic Klotho deficiency. Klotho deficiency renders the kidney more susceptible to acute insults, delays kidney regeneration, and promotes renal fibrosis. In addition to direct renal effects, Klotho deficiency also triggers and aggravates deranged mineral metabolism, secondary hyperparathyroidism, vascular calcification, and cardiac hypertrophy and fibrosis. Although studies examining the therapeutic effect of Klotho replacement were performed in animal models, it is quite conceivable that supplementation of exogenous Klotho and/or up-regulation of endogenous Klotho production may be a viable therapeutic strategy for patients with acute or chronic kidney diseases.
Seminars in Nephrology 03/2013; 33(2):118-29. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The metabolically active and perpetually remodeling calcium phosphate-based endoskeleton in terrestrial vertebrates sets the demands on whole-organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross talk. The fibroblast growth factor (FGF)-Klotho endocrine networks epitomize the complexity of systems biology, and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather than a passive target organ as hitherto conceived. Other than serving as a coreceptor for FGF23, αKlotho circulates as an endocrine substance with a multitude of effects. This review covers recent data on the physiological regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiological state in which FGF23-αKlotho, a multiorgan endocrine network, is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to its morbidity and mortality.
Annual Review of Physiology 02/2013; 75:503-33. · 20.83 Impact Factor
-
Jakob Voelkl,
Ioana Alesutan,
Christina B Leibrock,
Leticia Quintanilla-Martinez,
Volker Kuhn,
Martina Feger,
Sobuj Mia,
Mohamed S E Ahmed,
Kevin P Rosenblatt, Makoto Kuro-O,
Florian Lang
[show abstract]
[hide abstract]
ABSTRACT: Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH)2D3] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH)2D3, FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.
The Journal of clinical investigation 01/2013; · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: AIM: Suicidal erythrocyte death or eryptosis is characterized by cell shrinkage and phosphatidylserine exposure at the cell surface. Eryptotic erythrocytes may adhere to the vascular wall by binding of phosphatidylserine to endothelial CXC chemokine ligand 16 (CXCL16). Triggers of eryptosis include osmotic shock or energy depletion. Susceptibility to eryptosis is modified by Klotho, a protein with profound effect on aging and life span. Klotho deficiency leads to accelerated aging and early death. The percentage of eryptotic erythrocytes is significantly larger in klotho-deficient mice (klotho(-/-) ) than in their wild type littermates (klotho(+/+) ). The present study explored whether the accelerated eryptosis of klotho deficient mice is paralleled by enhanced adhesion METHODS: Phosphatidylserine exposing erythrocytes were identified by measurement of Annexin-V-binding and adhesion to human umbilical vein endothelial cells (HUVEC) from trapping of labeled erythrocytes in a flow chamber. RESULTS: Annexin-V-binding was higher in klotho(-/-) erythrocytes than in klotho(+/+) erythrocytes. Osmotic shock for 1 hour (addition of 550 mM sucrose) and energy depletion (12 hours glucose depletion) increased Annexin-V-binding to values again significantly larger in klotho(-/-) erythrocytes than in klotho(+/+) erythrocytes. Klotho(-/-) erythrocytes were particularly sensitive to osmotic shock. Both, osmotic shock and energy depletion enhanced erythrocyte adhesion, an effect again more pronounced in klotho(-/-) erythrocytes than in klotho(+/+) erythrocytes. The adhesion was significantly decreased by coating of phospatidylserine with annexin-V (5 μl/ml) or by coating CXCL16 with neutralizing antibodies (4 μg/ml). CONCLUSIONS: Klotho(-/-) erythrocytes are particularly sensitive to osmotic shock and enhanced eryptosis of klotho(-/-) erythrocytes is paralleled by enhanced adhesion to endothelial CXCL16. © 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.
Acta Physiologica 12/2012; · 3.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Klotho is a membrane protein predominantly produced in the kidney that exerts some antiageing effects. Ageing is associated with an increased risk of heart failure; whether Klotho is cardioprotective is unknown. Here we show that Klotho-deficient mice have no baseline cardiac abnormalities but develop exaggerated pathological cardiac hypertrophy and remodelling in response to stress. Cardioprotection by Klotho in normal mice is mediated by downregulation of TRPC6 channels in the heart. We demonstrate that deletion of Trpc6 prevents stress-induced exaggerated cardiac remodelling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodelling. Klotho overexpression ameliorates cardiac pathologies in these mice and improves their long-term survival. Soluble Klotho present in the systemic circulation inhibits TRPC6 currents in cardiomyocytes by blocking phosphoinositide-3-kinase-dependent exocytosis of TRPC6 channels. These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.
Nature Communications 12/2012; 3:1238. · 7.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mice lacking Klotho or fibroblast growth factor 23 (FGF23) exhibit a premature aging syndrome associated with abnormal mineral metabolism characterized by hyperphosphatemia, hypercalcemia, and hypervitaminosis D. Several genetic and dietary interventions that reduce blood phosphate, calcium, and/or vitamin D levels rescue the premature aging syndrome concomitantly. Notably, the rescue is always associated with decrease in blood phosphate levels, but not necessarily with decrease in calcium or vitamin D, suggesting that hyperphosphatemia is primarily responsible for the premature aging. Hyperphsophatemia, decreased Klotho expression, and aging-like symptoms are often manifested in patients with chronic kidney disease (CKD). Thus, CKD may be viewed as a premature aging syndrome caused by hyperphosphatemia and Klotho deficiency. Further clinical studies are required to verify the link between phosphate and aging and to apply this novel concept to anti-aging medicine.
Clinical calcium 10/2012; 22(10):1493-8.
-
[show abstract]
[hide abstract]
ABSTRACT: Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.Kidney International advance online publication, 29 August 2012; doi:10.1038/ki.2012.322.
Kidney International 08/2012; · 6.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Klotho is highly expressed in the kidney and a soluble form of Klotho functions as an endocrine substance that exerts multiple actions including the modulation of renal solute transport and the protection of the kidney from a variety of insults in experimental models. At present, the Klotho database is still largely preclinical, but the anticipated forthcoming impact on clinical nephrology can be immense. This manuscript puts these potentials into perspective for the clinician. There is renal and systemic Klotho deficiency in both acute kidney injury (AKI) and chronic kidney disease (CKD). Klotho plummets very early and severely in AKI and represents a pathogenic factor that exacerbates acute kidney damage. In CKD, Klotho deficiency exerts a significant impact on progression of renal disease and extra renal complications. In AKI, soluble Klotho levels in plasma and/or urine may serve as an early biomarker for kidney parenchymal injury. Restoration by exogenous supplementation or stimulation of endogenous Klotho may prevent and/or ameliorate kidney injury and mitigate CKD development. In CKD, Klotho levels may be an indicator of early disease and predict the rate of progression, and presence and severity of soft tissue calcification. The correction of Klotho deficiency may delay progression and forestall development of extra renal complications in CKD. Rarely does one find a molecule with such broad potential applications in nephrology. Klotho can possibly emerge on the horizon as a candidate for an unprecedented sole biomarker and intervention. Nephrologists should monitor the progress of the preclinical studies and the imminently emerging human database.
Nephrology Dialysis Transplantation 07/2012; 27(7):2650-7. · 3.40 Impact Factor
-
Regina Goetz,
Mutsuko Ohnishi,
Serkan Kir,
Hiroshi Kurosu,
Lei Wang,
Johanne Pastor,
Jinghong Ma,
Weiming Gai, Makoto Kuro-o,
Mohammed S Razzaque,
Moosa Mohammadi
[show abstract]
[hide abstract]
ABSTRACT: FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.
Journal of Biological Chemistry 06/2012; 287(34):29134-46. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The metabolically active and perpetually remodeling calcium phosphate-based endoskeleton in terrestrial vertebrates sets the demands on whole organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross-talk. The fibroblast growth factor-Klotho endocrine networks epitomizes the complexity of systems biology and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather a passive target organ as hitherto conceived. Other than serving as a co-receptor for FGF23, αKlotho also circulates as an endocrine substance with a multitude of effects. This articles reviews recent data on the physiologic regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiologic state where this multi-organ endocrine network is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to the morbidity and mortalit...
04/2012;
-
Regina Goetz,
Mutsuko Ohnishi,
Xunshan Ding,
Hiroshi Kurosu,
Lei Wang,
Junko Akiyoshi,
Jinghong Ma,
Weiming Gai,
Yisrael Sidis,
Nelly Pitteloud, Makoto Kuro-O,
Mohammed S Razzaque,
Moosa Mohammadi
[show abstract]
[hide abstract]
ABSTRACT: It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to αKlotho, βKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on βKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR.
Molecular and cellular biology 03/2012; 32(10):1944-54. · 6.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Klotho is a putative age-suppressing gene whose overexpression in mice results in extension of life span. The Klotho gene encodes a single-pass transmembrane protein whose extracellular domain is shed and released into blood, urine, and cerebrospinal fluid, potentially functioning as a humoral factor. The extracellular domain of Klotho has an activity that increases the expression of antioxidant enzymes and confers resistance to oxidative stress in cultured cells and in whole animals. The transmembrane form of the Klotho protein directly binds to multiple fibroblast growth factor receptors and modifies their ligand affinity and specificity. The purpose of the present study was to determine the precise cellular localization of Klotho in the mouse brain. Using light microscopic immunohistochemical methods, we found the highest levels of Klotho immunoreactivity in 2 brain regions: the choroid plexus, and cerebellar Purkinje cells. In the choroid plexus cells, Klotho was found not only on the plasma membrane but also in large amounts near the nuclear membrane. Likewise, in the Purkinje cell Klotho was found throughout the cell including dendrites, axon and soma with large amounts near the nuclear membrane. Using immunoelectron microscopy, we found Klotho in the cell membrane, but the highest concentration was localized in the peripheral portion of the nucleus and the nucleolus in both cell types. This new finding suggests that in addition to Klotho being secreted from cells in brain, it also has a nuclear function.
Neurobiology of aging 01/2012; 33(7):1483.e25-30. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Soluble Klotho (sKl) in the circulation can be generated directly by alterative splicing of the Klotho transcript or the extracellular domain of membrane Klotho can be released from membrane-anchored Klotho on the cell surface. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23), sKl, acts as hormonal factor and plays important roles in anti-aging, anti-oxidation, modulation of ion transport, and Wnt signaling. Emerging evidence reveals that Klotho deficiency is an early biomarker for chronic kidney diseases as well as a pathogenic factor. Klotho deficiency is associated with progression and chronic complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. In multiple experimental models, replacement of sKl, or manipulated up-regulation of endogenous Klotho protect the kidney from renal insults, preserve kidney function, and suppress renal fibrosis, in chronic kidney disease. Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.
Advances in experimental medicine and biology 01/2012; 728:126-57. · 1.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Normal human colonic epithelial cells (HCECs) are not immortalized by telomerase alone but also require CDK4. Some human cell types growth-arrest due to stress- or aberrant signaling-induced senescence (stasis). Stasis represents the consequences of growth conditions culture that are inadequate to maintain long-term proliferation. Overexpressed CDK4 titers out p16 and allows cells to ignore the growth arrest signals produced by stasis. To identify factors contributing to the inadequate culture environment, we used a 62,000-member shRNA library to knock down factors cooperating with human telomerase reverse transcriptase (hTERT) in the immortalization of HCECs. Knockdown of Klotho gamma (KLG; also known as KLPH and LCTL) allowed hTERT to immortalize HCECs. KLG is one isoform of the Klotho family of factors that coordinate interaction between different FGF ligands and the FGF receptor. We also found that knockdown of KLG induced another member of the Klotho family, Klotho beta (KLB). Induction of KLB was maintained and could activate ERK1/2 in immortalized cells. Supplementation of the culture medium with the KLB ligand FGF19 had a similar effect on hTERT-expressing HCECs as knockdown of KLG regarding both immortalization and down-regulation of the tumor suppressor Klotho alpha. Together, these data suggest that KLB is an important regulator in the immortalization of HCECs by facilitating FGF19 growth factor signaling.
Journal of Biological Chemistry 12/2011; 286(50):43294-300. · 4.77 Impact Factor
-
Christian Faul,
Ansel P Amaral,
Behzad Oskouei,
Ming-Chang Hu,
Alexis Sloan,
Tamara Isakova,
Orlando M Gutiérrez,
Robier Aguillon-Prada,
Joy Lincoln,
Joshua M Hare, [......],
Stefan Reuter,
Dominik Kentrup,
Klaus Tiemann,
Marcus Brand,
Joseph A Hill,
Orson W Moe, Makoto Kuro-O,
John W Kusek,
Martin G Keane,
Myles Wolf
[show abstract]
[hide abstract]
ABSTRACT: Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
The Journal of clinical investigation 11/2011; 121(11):4393-408. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Normal human colonic epithelial cells (HCEC) are not immortalized by telomerase alone but also require CDK4. Some human cell
types growth arrest due to stress or aberrant signaling induced senescence (stasis). Stasis represents the consequences of
growth conditions in culture that are inadequate to maintain long-term proliferation. Overexpressed CDK4 titers out p16 and
allows cells to ignore the growth arrest signals produced by stasis. In order to identify factors contributing to the inadequate
culture environment, we used a 62,000 member shRNA library to knock down factors cooperating with hTERT in the immortalization
of HCECs. Knockdown of Klotho gamma (KLG: also known as KLPH, LCTL) allowed hTERT to immortalize HCEC cells. KLG is one isoform
of the Klotho family of factors that coordinate interaction between different FGF ligands and the FGF receptor. We also found
that knockdown of KLG induced another member of the Klotho family, Klotho beta (KLB). Induction of KLB was maintained and
can activate ERK1/2 in immortalized cells. Supplementation of the culture medium with the KLB ligand FGF19 had a similar effect
on hTERT expressing HCEC as knock down of KLG, both regarding immortalization and the down regulation of the tumor suppressor
Klotho alpha (KLA). Together, these data suggest that KLB is an important regulator in the immortalization of HCEC cells by
facilitating FGF19 growth factor signaling.
Journal of Biological Chemistry 10/2011; · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT: An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states is presented. The signals are amplified linearly by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots, but are not linear by the enzyme-based amplification. Software is developed to facilitate the quantitative readouts of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.
Proteome Science 09/2011; 9:53. · 2.33 Impact Factor
-
Hongwei Wang,
Madhukumar Venkatesh,
Hao Li,
Regina Goetz,
Subhajit Mukherjee,
Arunima Biswas,
Liang Zhu,
Andreas Kaubisch,
Lei Wang,
James Pullman,
Kathleen Whitney, Makoto Kuro-o,
Andres I Roig,
Jerry W Shay,
Moosa Mohammadi,
Sridhar Mani
[show abstract]
[hide abstract]
ABSTRACT: The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and "normal" intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.
The Journal of clinical investigation 08/2011; 121(8):3220-32. · 15.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The klotho gene (KL) was identified first as a putative aging-suppressor gene that extended life span when overexpressed and accelerated aging-like phenotypes when disrupted in mice. It encodes a single-pass transmembrane protein and is expressed predominantly in kidney, where it functions as an obligate coreceptor for fibroblast growth factor 23 (FGF-23). FGF-23 is a bone-derived hormone that suppresses phosphate reabsorption and 1,25 dihydroxyvitamin D(3) (vitamin D) synthesis in the kidney. Klotho also is expressed in the parathyroid gland, where FGF-23 decreases parathyroid hormone expression and secretion, further suppressing vitamin D synthesis in kidney. Thus, FGF-23 functions as a phosphaturic hormone and a counter-regulatory hormone for vitamin D, thereby inducing negative phosphate balance. Mice lacking either FGF-23 or Klotho show hyperphosphatemia in addition to developing multiple aging-like phenotypes, which can be rescued by resolving phosphate retention. These findings have unveiled an unexpected link between aging and phosphate. In patients with chronic kidney disease (CKD), phosphate retention is seen universally and has been associated with increased mortality risk. Patients with CKD have high serum FGF-23 levels with decreased klotho expression in the kidney and parathyroid, rendering FGF-23 and Klotho as potential biomarkers and therapeutic targets for CKD. The Klotho protein not only serves as a coreceptor for FGF-23, but also functions as a humoral factor. Klotho's extracellular domain is released into blood and urine by ectodomain shedding and exerts various functions independently of FGF-23, including regulation of multiple ion channels and transporters. Decreased urinary Klotho protein level has been identified as one of the earliest biomarkers of CKD progression. This review focuses on the current understanding of Klotho protein function, with emphasis on its potential involvement in the pathophysiologic process of CKD.
American Journal of Kidney Diseases 07/2011; 58(1):127-34. · 5.43 Impact Factor
-
Mentor Sopjani,
Ioana Alesutan,
Miribane Dërmaku-Sopjani,
Shuchen Gu,
Christine Zelenak,
Carlos Munoz,
Ana Velic,
Michael Föller,
Kevin P Rosenblatt, Makoto Kuro-o,
Florian Lang
[show abstract]
[hide abstract]
ABSTRACT: Klotho-hypomorphic (Klotho(hm)) mice suffer from renal salt wasting and hypovolemia despite hyperaldosteronism. The present study explored the effect of Klotho on renal Na(+)/K(+) ATPase activity. According to immunohistochemistry and confocal microscopy Na(+)/K(+) ATPase protein abundance in isolated collecting ducts was lower in Klotho(hm) mice than in their wild type littermates (Klotho(+/+)). Analysis with dual electrode voltage clamp recording showed that expression of Klotho in Xenopus oocytes increased the Na(+)/K(+) ATPase pump current. Treatment of Xenopus oocytes with Klotho protein similarly increased the pump current. In conclusion, Klotho increases the membrane abundance and activity of the Na(+)/K(+) ATPase. Decreased Na(+)/K(+) ATPase activity could thus contribute to the volume-depletion of klotho(hm) mice.
FEBS letters 06/2011; 585(12):1759-64. · 3.54 Impact Factor
