title: Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.
abstract: Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-β1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Departments of Internal Medicine, ming-chang.hu@utsouthwestern.edu orson.moe@utsouthwestern.edu.
authors.forename: Ming Chang
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Han Jun
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Departments of Internal Medicine, Clinical Sciences.
authors.forename: Beverley
authors.initials: B
authors.lastname: Adams-Huet
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Jean
authors.initials: J
authors.lastname: Paek
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research.
authors.forename: Kathy
authors.initials: K
authors.lastname: Hill
authors.affiliation: Pathology.
authors.forename: John
authors.initials: J
authors.lastname: Shelton
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Ansel P
authors.initials: AP
authors.lastname: Amaral
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Clinical Sciences.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine D, University of Münster, Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Brand
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Pathology.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.affiliation: Departments of Internal Medicine, Molecular Biology, and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Departments of Internal Medicine, Physiology, and ming-chang.hu@utsouthwestern.edu orson.moe@utsouthwestern.edu.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D006332:Cardiomegaly / Q000097:blood* / Q000453:epidemiology / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000097:blood / Q000473:pathology; D005966:Glucuronidase / Q000097:blood / Q000378:metabolism*; D006334:Heart Function Tests; D000090265:Klotho Proteins; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D010710:Phosphates / Q000097:blood* / Q000378:metabolism; D011897:Random Allocation; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology / Q000378:metabolism; D012680:Sensitivity and Specificity; D014511:Uremia / Q000097:blood / Q000453:epidemiology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D015415:Biomarkers; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: CKD; heart disease; hypertrophy; ischemia-reperfusion; transgenic mouse; uremia