Abstract
Recent studies have identified a novel bone−kidney endocrine axis that maintains phosphate homeostasis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on the kidney to promote phosphate excretion into urine and suppress vitamin D synthesis, thereby inducing negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate coreceptor to bind and activate FGF receptors. Several hereditary disorders that exhibit inappropriately high serum FGF23 levels are associated with phosphate wasting and impaired bone mineralization. In contrast, defects in either FGF23 or Klotho are associated with phosphate retention and a premature-aging syndrome. The aging-like phenotypes in Klotho-deficient or FGF23-deficient mice can be rescued by resolving hyperphosphatemia with dietary or genetic manipulation, suggesting a novel concept that phosphate retention accelerates aging. Phosphate retention is universally observed in patients with chronic kidney disease (CKD) and identified as a potent risk of death in epidemiological studies. Thus, the bone−kidney endocrine axis mediated by FGF23 and Klotho has emerged as a novel target of therapeutic interventions in CKD.
Similar content being viewed by others
References
Berndt T, Kumar R (2009) Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda) 24:17–25
Dusso AS, Brown AJ, Slatopolsky E (2005) Vitamin D. Am J Physiol Renal Physiol 289:F8–F28
Berndt T, Kumar R (2007) Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 69:341–359
Kuro-o M (2006) Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 15:437–441
White KE, Evans WE, O'Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Storm TM (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348
Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828
Quarles LD (2003) FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 285:E1–E9
Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17:1305–1315
Liu S, Gupta A, Quarles LD (2007) Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization. Curr Opin Nephrol Hypertens 16:329–335
Kuro-o M (2009) Klotho in chronic kidney disease-What’s new? Nephrol Dial Transplant 24:1705–1708
White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ (2001) Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60:2079–2086
Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143:3179–3182
Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98:6500–6505
The HYP Consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet 11:130–136
Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38:1310–1315
Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, Olivares JL, Loris C, Ramos FJ, Glorieux F, Vikkula M, Juppner H, Strom TM (2006) DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248–1250
Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS (1997) Pex/PEX tissue distribution and evidence for a deletion in the 3′ region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest 99:1200–1209
Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38–E49
Garringer HJ, Fisher C, Larsson TE, Davis SI, Koller DL, Cullen MJ, Draman MS, Conlon N, Jain A, Fedarko NS, Dasgupta B, White KE (2006) The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. J Clin Endocrinol Metab 91:4037–4042
Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem 281:18370–18377
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568
Yamashita T, Yoshioka M, Itoh N (2000) Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277:494–498
Itoh N, Ornitz DM (2008) Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 237:18–27
Kuro-o M (2008) Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 19:239–245
Murzin AG, Lesk AM, Chothia C (1992) beta-Trefoil fold. Patterns of structure and sequence in the Kunitz inhibitors interleukins-1 beta and 1 alpha and fibroblast growth factors. J Mol Biol 223:531–543
Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137
Mohammadi M, Olsen SK, Goetz R (2005) A protein canyon in the FGF-FGF receptor dimer selects from an a la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 15:506–516
Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL (2004) The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry 43:629–640
Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert T, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M (2007) Molecular insights into the Klotho-dependent, endocrine mode of action of FGF19 subfamily members. Mol Cell Biol 27:3417–3428
Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M (2000) Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 6:743–750
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima Y (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
Min D, Panoskaltsis-Mortari A, Kuro-o M, Hollander GA, Blazar BR, Weinberg KI (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109:2529–2537
Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M (1999) Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. J Clin Invest 104:229–237
Suga T, Kurabayashi M, Sando Y, Ohyama Y, Maeno T, Maeno Y, Aizawa H, Matsumura Y, Kuwaki T, Kuro-o M, Nabeshima Y, Nagai R (2000) Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. Am J Respir Cell Mol Biol 22:26–33
Sato A, Hirai T, Imura A, Kita N, Iwano A, Muro S, Nabeshima Y, Suki B, Mishima M (2007) Morphological mechanism of the development of pulmonary emphysema in klotho mice. Proc Natl Acad Sci U S A 104:2361–2365
Ishii M, Yamaguchi Y, Yamamoto H, Hanaoka Y, Ouchi Y (2008) Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. J Gerontol A Biol Sci Med Sci 63:1289–1298
Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17:50–52
Kamemori M, Ohyama Y, Kurabayashi M, Takahashi K, Nagai R, Furuya N (2002) Expression of Klotho protein in the inner ear. Hear Res 171:103–110
Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S, Kawakami E, Kanda N, Matsubara S, Kuro-o M, Nabeshima Y, Nakamura K, Oyanagi K (2005) Klotho insufficiency causes decrease of ribosomal RNA gene transcription activity, cytoplasmic RNA and rough ER in the spinal anterior horn cells. Acta Neuropathol (Berl) 109:457–466
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833
Kuro-o M (2008) Klotho as a regulator of oxidative stress and senescence. Biol Chem 389:233–241
Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC (2002) Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A 99:856–861
Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H (2002) Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 17:1744–1751
Ogata N, Matsumura Y, Shiraki M, Kawano K, Koshizuka Y, Hosoi T, Nakamura K, Kuro-o M, Kawaguchi H (2002) Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. Bone 31:37–42
Zarrabeitia MT, Hernandez JL, Valero C, Zarrabeitia AL, Ortiz F, Gonzalez-Macias J, Riancho JA (2007) Klotho gene polymorphism and male bone mass. Calcif Tissue Int 80:10–14
Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 96:412–418
Arking DE, Becker DM, Yanek LR, Fallin D, Judge DP, Moy TF, Becker LC, Dietz HC (2003) KLOTHO allele status and the risk of early-onset occult coronary artery disease. Am J Hum Genet 72:1154–1161
Kachiwala SJ, Harris SE, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ (2005) Genetic influences on oxidative stress and their association with normal cognitive ageing. Neurosci Lett 386:116–120
Mian IS (1998) Sequence, structural, functional, and phylogenetic analyses of three glycosidase families. Blood Cells Mol Dis 24:83–100
Tohyama O, Imura A, Iwano A, Freund JN, Henrissat B, Fujimori T, Nabeshima Y (2004) Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 279:9777–9784
Yoshida T, Fujimori T, Nabeshima Y (2002) Mediation of unusually high concentrations of 1, 25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene. Endocrinology 143:683–689
Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y (2003) Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17:2393–2403
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774
Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS (2009) In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23)-mediated regulation of systemic phosphate homeostasis. FASEB J 23:433–441
Kurosu H, Kuro-o M (2009) The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol 299:72–78
Kurosu H, Kuro-o M (2008) The Klotho gene family and the endocrine fibroblast growth factors. Curr Opin Nephrol Hypertens 17:368–372
Liu S, Quarles LD (2007) How fibroblast growth factor 23 works. J Am Soc Nephrol 18:1637–1647
Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K (2003) Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch 446:585–592
Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, Imura A, Nabeshima Y, Miyamoto K (2007) Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice. Am J Physiol Renal Physiol 292:F769–F779
Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2004) FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314:409–414
Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H (2007) New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. Am J Nephrol 27:503–515
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435
Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2692–2701
Liu S, Vierthaler L, Tang W, Zhou J, Quarles LD (2008) FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol 19:2342–2350
Farrow EG, Davis SI, Summers LJ, White KE (2009) Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20:955–960
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008
Krajisnik T, Bjorklund P, Marsell R, Ljunggren O, Akerstrom G, Jonsson KB, Westin G, Larsson TE (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131
Stubbs JR, Liu S, Tang W, Zhou J, Wang Y, Yao X, Quarles LD (2007) Role of hyperphosphatemia and 1,25-Dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. J Am Soc Nephrol 18:2116–2124
Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B (2006) Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 20:720–722
Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1 alpha-hydroxylase. Kidney Int 75:1166–1172
Hesse M, Frohlich LF, Zeitz U, Lanske B, Erben RG (2007) Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol 26:75–84
Morishita K, Shirai A, Kubota M, Katakura Y, Nabeshima Y, Takeshige K, Kamiya T (2001) The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 131:3182–3188
Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633
Hruska KA, Saab G, Mathew S, Lund R (2007) Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Semin Dial 20:309–315
Meyer KB, Levey AS (1998) Controlling the epidemic of cardiovascular disease in chronic renal disease: report from the National Kidney Foundation Task Force on cardiovascular disease. J Am Soc Nephrol 9:S31–S42
Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW (2003) Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108:2154–2169
Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK (2001) Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 12:2131–2138
Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215
Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki T, Nabeshima Y (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020
Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS (2007) Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci U S A 104:2331–2336
Sugiura H, Yoshida T, Tsuchiya K, Mitobe M, Nishimura S, Shirota S, Akiba T, Nihei H (2005) Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant 20:2636–2645
Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359:584–592
Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R (2002) In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39:838–843
Saito K, Ishizaka N, Mitani H, Ohno M, Nagai R (2003) Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat. FEBS Lett 551:58–62
Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y, Chien S, Wang N (2008) Klotho is a target gene of PPAR-gamma. Kidney Int 74:732–739
Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 104:19796–19801
Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147
Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG (2005) The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310:490–493
Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-o M, Huang CL (2008) Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 105:9805–9810
Cha SK, Hu MC, Kurosu H, Kuro-o M, Moe O, Huang CL (2009) Regulation of ROMK1 channel and renal K + excretion by Klotho. Mol Pharmacol. doi:10.1124/mol.109.055780