The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy

Current Opinion in Nephrology and Hypertension

Volumn 25, Issue 4, 2016, Pages 314-324

  Grabner, Alexander ^a   Faul, Christian ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

cardiac hypertrophy; fibroblast growth factor 23; Klotho; uremic cardiomyopathy

Indexed keywords

CALCINEURIN; FIBROBLAST GROWTH FACTOR 23; FIBROBLAST GROWTH FACTOR RECEPTOR 4; KLOTHO PROTEIN; MESSENGER RNA; TRANSCRIPTION FACTOR NFAT; BETA GLUCURONIDASE; FIBROBLAST GROWTH FACTOR; PHOSPHATE;

CARDIOMYOPATHY; CHRONIC KIDNEY DISEASE; ENZYME LINKED IMMUNOSORBENT ASSAY; HEART; HEART VENTRICLE HYPERTROPHY; HUMAN; IMMUNOPRECIPITATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; UREMIC CARDIOMYOPATHY; CARDIAC MUSCLE; CARDIOMEGALY; CHRONIC KIDNEY FAILURE; COMPLICATION; METABOLISM; UREMIA;

CARDIOMEGALY; CARDIOMYOPATHIES; FIBROBLAST GROWTH FACTORS; GLUCURONIDASE; HUMANS; MYOCARDIUM; PHOSPHATES; RENAL INSUFFICIENCY, CHRONIC; UREMIA;

EID: 84969988387     PISSN: 10624821     EISSN: 14736543     Source Type: Journal    
DOI: 10.1097/MNH.0000000000000231     Document Type: Review

References (136)

1. London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. J Am Soc Nephrol 2001; 12:2759-2767.
2. Di Lullo L, Gorini A, Russo D, et al. Left ventricular hypertrophy in chronic kidney disease patients: from pathophysiology to treatment. Cardiorenal Med 2015; 5:254-266.
3. Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol 2001; 12:1079-1084.
4. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA 2005; 293:1737-1745.
5. Zoccali C, Benedetto FA, Mallamaci F, et al. Prognostic value of echocardiographic indicators of left ventricular systolic function in asymptomatic dialysis patients. J Am Soc Nephrol 2004; 15:1029-1037.
6. Appel LJ, Wright JT Jr, Greene T, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010; 363:918-929.
7. de Boer IH, Rue TC, Hall YN, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011; 305:2532-2539.
8. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2012; 377:2181-2192.
9. Lowrie EG, Huang WH, Lew NL. Death risk predictors among peritoneal dialysis and hemodialysis patients: a preliminary comparison. Am J Kidney Dis 1995; 26:220-228.
10. Zager PG, Nikolic J, Brown RH, et al. "U" curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc. Kidney Int 1998; 54:561-569.
11. Winchester JF, Audia PF. Extracorporeal strategies for the removal of middle molecules. Semin Dial 2006; 19:110-114.
12. Lekawanvijit S, Kompa AR, Wang BH, et al. Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res 2012; 111:1470-1483.
13. Shane E, Mancini D, Aaronson K, et al. Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure. Am J Med 1997; 103:197-207.
14. Zittermann A, Schleithoff SS, Tenderich G, et al. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol 2003; 41:105-112.
15. Pilz S, Tomaschitz A, Marz W, et al. Vitamin D, cardiovascular disease and mortality. Clin Endocrinol (Oxf) 2011; 75:575-584.
16. Schierbeck LL, Jensen TS, Bang U, et al. Parathyroid hormone and vitamin D-markers for cardiovascular and all cause mortality in heart failure. Eur J Heart Fail 2011; 13:626-632.
17. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15:2208-2218.
18. Benet-Pages A, Lorenz-Depiereux B, Zischka H, et al. FGF23 is processed by proprotein convertases but not by PHEX. Bone 2004; 35:455-462.
19. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008; 118:3820-3828.
20. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390:45-51.
21. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770-774.
22. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19:429-435.
23. Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004; 314:409-414.
24. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007; 117:4003-4008.
25. Saito H, Maeda A, Ohtomo S, et al. Circulating FGF-23 is regulated by 1alpha, 25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005; 280:2543-2549.
26. Saito H, Kusano K, Kinosaki M, et al. Human fibroblast growth factor-23 mutants suppress Na\+-dependent phosphate co-transport activity and 1alpha, 25-dihydroxyvitaminD3production. J BiolChem2003; 278: 2206-2211.
27. Isakova T, Gutierrez OM, Wolf M. A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease. Kidney Int 2009; 76:705-716.
28. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79:1370-1378.
29. Hasegawa H, Nagano N, Urakawa I, et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int 2010; 78:975-980.
30. Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119:2545-2552.
31. Seiler S, Reichart B, Roth D, et al. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant 2010; 25:3983-3989.
32. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359:584-592.
33. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305:2432-2439.
34. Kendrick J, Cheung AK, Kaufman JS, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2010; 22:1913-1922.
35. Hsu HJ, Wu MS. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 2009; 337:116-122.
36. Kirkpantur A, Balci M, Gurbuz OA, et al. Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol Dial Transplant 2011; 26:1346-1354.
37. Seeherunvong W, Abitbol CL, Chandar J, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr Nephrol 2012; 27:2129-2136.
38. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121:4393-4408.
39. Hu MC, Shi M, Cho HJ, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 2015; 26:1290-1302.
40. Shobeiri N, Pang J, Adams MA, Holden RM. Cardiovascular disease in an adenine-induced model of chronic kidney disease: the temporal link between vascular calcification and haemodynamic consequences. J Hypertens 2013; 31:160-168.
41. Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004; 113:561-568.
42. Shalhoub V, Shatzen EM, Ward SC, et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012; 122:2543-2553.
43. Touchberry CD, Green TM, Tchikrizov V, et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am J Physiol Endocrinol Metab 2013; 304:E863-E873.
44. Grabner A, Amaral AP, Schramm K, et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab 2015; 22:1020-1032.
45. Wilkins BJ, Dai YS, Bueno OF, et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 2004; 94:110-118.
46. Di Marco GS, Reuter S, Kentrup D, et al. Cardioprotective effect of calcineurin inhibition in an animal model of renal disease. Eur Heart J 2011; 32:1935-1945.
47. Leifheit-Nestler M, Grosse Siemer R, Flasbart K, et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transplant 2015; doi: 10. 1093/ndt/gfv421. [Epub ahead of print]
48. Moe SM, Chertow GM, Parfrey PS, et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the Evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) Trial. Circulation 2015; 132:27-39.
49. Nehgme R, Fahey JT, Smith C, Carpenter TO. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 1997; 82:2450-2454.
50. Andrukhova O, Slavic S, Smorodchenko A, et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 2014; 6:744-759.
51. Seiler S, Cremers B, Rebling NM, et al. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur Heart J 2011; 32:2688-2696.
52. Isakova T, Houston J, Santacruz L, et al. Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. Pediatr Nephrol 2013; 28:2035-2042.
53. Shibata K, Fujita S, Morita H, et al. Association between circulating fibroblast growth factor 23, alpha-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS One 2013; 8:e73184.
54. Imazu M, Takahama H, Asanuma H, et al. Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease. Am J Physiol Heart Circ Physiol 2014; 307:H1504-1511.
55. Wohlfahrt P, Melenovsky V, Kotrc M, et al. Association of fibroblast growth factor-23 levels and angiotensin-converting enzyme inhibition in chronic systolic heart failure. JACC Heart Fail 2015; 3:829-839.
56. Andersen IA, Huntley BK, Sandberg SS, et al. Elevation of circulating but not myocardial FGF23 in human acute decompensated heart failure. Nephrol Dial Transplant 2015; doi: 10. 1093/ndt/gfv398. [Epub ahead of print]
57. Andrukhova O, Slavic S, Odorfer KI, Erben RG. Experimental myocardial infarction upregulates circulating fibroblast growth factor-23. J Bone Miner Res 2015; 30:1831-1839.
58. Agarwal I, Ide N, Ix JH, et al. Fibroblast growth factor-23 and cardiac structure and function. J Am Heart Assoc 2014; 3:e000584.
59. Unsal A, Kose Budak S, Koc Y, et al. Relationship of fibroblast growth factor 23 with left ventricle mass index and coronary calcificaton in chronic renal disease. Kidney Blood Press Res 2012; 36:55-64.
60. Sinha MD, Turner C, Booth CJ, et al. Relationship of FGF23 to indexed left ventricular mass in children with nondialysis stages of chronic kidney disease. Pediatr Nephrol 2015; 30:1843-1852.
61. Maizel J, Six I, Dupont S, et al. Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure. Kidney Int 2013; 84:491-500.
62. Chue CD, Townend JN, Moody WE, et al. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol 2013; 24:842-852.
63. Dai B, David V, Martin A, et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One 2012; 7:e44161.
64. Han X, Li L, Yang J, et al. Counter-regulatory paracrine actions of FGF-23 and 1, 25(OH)2 D in macrophages. FEBS Lett 2016; 590:53-67.
65. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281:6120-6123.
66. Goetz R, Ohnishi M, Kir S, et al. Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. J Biol Chem 2012; 287:29134-29146.
67. Pavik I, Jaeger P, Ebner L, et al. Secreted Klotho and FGF23 in chronic kidney disease stage 1 to 5: a sequence suggested from a cross-sectional study. Nephrol Dial Transplant 2013; 28:352-359.
68. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22:124-136.
69. Kitagawa M, Sugiyama H, Morinaga H, et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 2013; 8:e56695.
70. Mitani H, Ishizaka N, Aizawa T, et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 2002; 39:838-843.
71. Zhou Q, Lin S, Tang R, et al. Role of fosinopril and valsartan on klotho gene expression induced by angiotensin II in rat renal tubular epithelial cells. Kidney Blood Press Res 2010; 33:186-192.
72. Yoon HE, Ghee JY, Piao S, et al. Angiotensin II blockade upregulates the expression of Klotho, the antiageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant 2011; 26:800-813.
73. Saito K, Ishizaka N, Mitani H, et al. Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an antiaging gene, in rat. FEBS Lett 2003; 551:58-62.
74. Ohyama Y, Kurabayashi M, Masuda H, et al. Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress. Biochem Biophys Res Commun 1998; 251:920-925.
75. Thurston RD, Larmonier CB, Majewski PM, et al. Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology 2010; 138:1384-1394.
76. Radhakrishnan VM, Ramalingam R, Larmonier CB, et al. Post-translational loss of renal TRPV5 calcium channel expression, Ca(2\+) wasting, and bone loss in experimental colitis. Gastroenterology 2013; 145:613-624.
77. Moreno JA, Izquierdo MC, Sanchez-Nino MD, et al. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J Am Soc Nephrol 2011; 22:1315-1325.
78. Lau WL, Leaf EM, Hu MC, et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 2012; 82:1261-1270.
79. Forster RE, Jurutka PW, Hsieh JC, et al. Vitamin D receptor controls expression of the antiaging klotho gene in mouse and human renal cells. Biochem Biophys Res Commun 2011; 414:557-562.
80. Ritter CS, Zhang S, Delmez J, et al. Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats. Kidney Int 2015; 87:1141-1152.
81. Sugiura H, Yoshida T, Mitobe M, et al. Recombinant human erythropoietin mitigates reductions in renal klotho expression. Am J Nephrol 2010; 32:137-144.
82. Leone F, Lofaro D, Gigliotti P, et al. Soluble Klotho levels in adult renal transplant recipients are modulated by recombinant human erythropoietin. J Nephrol 2014; 27:577-585.
83. Faul C, Wolf M. Hunt for the culprit of cardiovascular injury in kidney disease. Cardiovasc Res 2015; 108:209-211.
84. Lewin E, Olgaard K. The vascular secret of Klotho. Kidney Int 2015; 87:1089-1091.
85. Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 1998; 242:626-630.
86. Shiraki-Iida T, Aizawa H, Matsumura Y, et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett 1998; 424:6-10.
87. Imura A, Iwano A, Tohyama O, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565:143-147.
88. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309:1829-1833.
89. Bloch L, Sineshchekova O, Reichenbach D, et al. Klotho is a substrate for alpha-, beta-and gamma-secretase. FEBS Lett 2009; 583:3221-3224.
90. Chen CD, Podvin S, Gillespie E, et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 2007; 104:19796-19801.
91. Lindberg K, Amin R, Moe OW, et al. The kidney is the principal organ mediating klotho effects. J Am Soc Nephrol 2014; 25:2169-2175.
92. Hu MC, Shi M, Zhang J, et al. Renal production, uptake, and handling of circulating aKlotho. J Am Soc Nephrol 2016; 27:79-90.
93. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the antiaging hormone klotho. J Biol Chem 2005; 280:38029-38034.
94. Ikushima M, Rakugi H, Ishikawa K, et al. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 2006; 339:827-832.
95. Maekawa Y, Ohishi M, Ikushima M, et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway. Geriatr Gerontol Int 2011; 11:510-516.
96. Buendia P, Carracedo J, Soriano S, et al. Klotho prevents NFkappaB translocation and protects endothelial cell from senescence induced by uremia. J Gerontol A Biol Sci Med Sci 2015; 70:1198-1209.
97. Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell 2012; 11:410-417.
98. Banerjee S, Zhao Y, Sarkar PS, et al. Klotho ameliorates chemically induced endoplasmic reticulum (ER) stress signaling. Cell Physiol Biochem 2013; 31:659-672.
99. Six I, Okazaki H, Gross P, et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One 2014; 9:e93423.
100. Maekawa Y, Ishikawa K, Yasuda O, et al. Klotho suppresses TNF-alphainduced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine 2009; 35:341-346.
101. Zeng Y, Wang PH, Zhang M, Du JR. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-kappaB signaling pathway in senescence-accelerated mice. Aging Clin Exp Res 2016; 28:69-76.
102. Zhao Y, Banerjee S, Dey N, et al. Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes 2011; 60:1907-1916.
103. Guan X, Nie L, He T, et al. Klotho suppresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling. J Pathol 2014; 234:560-572.
104. Chateau MT, Araiz C, Descamps S, Galas S. Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. Aging (Albany NY) 2010; 2:567-581.
105. Abramovitz L, Rubinek T, Ligumsky H, et al. KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin Cancer Res 2011; 17:4254-4266.
106. Xie J, Cha SK, An SW, et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 2012; 3:1238.
107. Liu H, Fergusson MM, Castilho RM, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317:803-806.
108. Satoh M, Nagasu H, Morita Y, et al. Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol 2012; 303:F1641-F1651.
109. Doi S, Zou Y, Togao O, et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011; 286:8655-8665.
110. Hu MC, Shi M, Cho HJ, et al. The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. Kidney Int 2013; 84:468-481.
111. Zhou L, Li Y, Zhou D, et al. Loss of Klotho contributes to kidney injury by derepression of Wnt/beta-catenin signaling. J Am Soc Nephrol 2013; 24:771-785.
112. Manya H, Inomata M, Fujimori T, et al. Klotho protein deficiency leads to overactivation of mu-calpain. J Biol Chem 2002; 277:35503-35508.
113. Nabeshima Y, Washida M, Tamura M, et al. Calpain 1 inhibitor BDA-410 ameliorates alpha-klotho-deficiency phenotypes resembling human agingrelated syndromes. Sci Rep 2014; 4:5847.
114. Tohyama O, Imura A, Iwano A, et al. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 2004; 279:9777-9784.
115. Hu MC, Shi M, Zhang J, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24:3438-3450.
116. Barker SL, Pastor J, Carranza D, et al. The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol Dial Transplant 2015; 30:223-233.
117. Sakan H, Nakatani K, Asai O, et al. Reduced renal alpha-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. PLoS One 2014; 9:e86301.
118. Xie J, Yoon J, An SW, et al. Soluble Klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 2015; 26:1150-1160.
119. Yang K, Wang C, Nie L, et al. Klotho protects against indoxyl sulphateinduced myocardial hypertrophy. J Am Soc Nephrol 2015; 26:2434-2446.
120. Fu H, Liu Y. Loss of Klotho in CKD breaks one's heart. J Am Soc Nephrol 2015; 26:2305-2307.
121. Floege J, Fliser D. Klotho deficiency and the cardiomyopathy of advanced CKD. J Am Soc Nephrol 2015; 26:1229-1231.
122. Song S, Si LY. Klotho ameliorated isoproterenol-induced pathological changes in cardiomyocytes via the regulation of oxidative stress. Life Sci 2015; 135:118-123.
123. Jia Z, Wei L, Liu Q, et al. [Impact of transfection with recombinant adenovirus vector-mediated Klotho gene on myocardial remodeling in a rat model of heart failure]. Zhonghua Xin Xue Guan Bing Za Zhi 2015; 43:219-226.
124. Song S, Gao P, Xiao H, et al. Klotho suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress. PLoS One 2013; 8:e82968.
125. Ai F, Chen M, Li W, et al. Protective role of Klotho on cardiomyocytes upon hypoxia/reoxygenation via downregulation of Akt and FOXO1 phosphorylation. Mol Med Rep 2015; 11:2013-2019.
126. Kuwahara K, Wang Y, McAnally J, et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 2006; 116:3114-3126.
127. Seiler S, Wen M, Roth HJ, et al. Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease. Kidney Int 2013; 83:121-128.
128. Buiten MS, de Bie MK, Bouma-de Krijger A, et al. Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol 2014; 15:197.
129. Brandenburg VM, Kleber ME, Vervloet MG, et al. Soluble klotho and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis 2015; 242:483-489.
130. Kato Y, Arakawa E, Kinoshita S, et al. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun 2000; 267:597-602.
131. Adema AY, Vervloet MG, Blankenstein MA, Heijboer AC. alpha-Klotho is unstable in human urine. Kidney Int 2015; 88:1442-1444.
132. Kawai M. The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. Horm Mol Biol Clin Investig 2016; doi: 10. 1515/hmbci-2015-0068. [Epub ahead of print]
133. Goetz R, Nakada Y, Hu MC, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci USA 2010; 107:407-412.
134. Sidhu S. Circulating Klotho levels: best way to measure and how to interpret existing data. In: American Society of Nephrology-Kidney Week; San Diego, CA; 2015.
135. Smith RC, O'Bryan LM, Farrow EG, et al. Circulating alphaKlotho influences phosphate handling by controlling FGF23 production. J Clin Invest 2012; 122:4710-4715.
136. Olauson H, Lindberg K, Amin R, et al. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 2013; 9:e1003975