title: Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate.
abstract: Cardiac hypertrophy occurs in up to 95% of patients with CKD and increases their risk for cardiovascular death. In the kidney, full-length membranous Klotho forms the coreceptor for fibroblast growth factor 23 (FGF23) to regulate phosphate metabolism. The prevailing view is that the decreased level of Klotho in CKD causes cardiomyopathy through increases in serum FGF23 and/or phosphate levels. However, we reported recently that soluble Klotho protects against cardiac hypertrophy by inhibiting abnormal calcium signaling in the heart. Here, we tested whether this protective effect requires changes in FGF23 and/or phosphate levels. Heterozygous Klotho-deficient CKD mice exhibited aggravated cardiac hypertrophy compared with wild-type CKD mice. Cardiac magnetic resonance imaging studies revealed that Klotho-deficient CKD hearts had worse functional impairment than wild-type CKD hearts. Normalization of serum phosphate and FGF23 levels by dietary phosphate restriction did not abrogate the aggravated cardiac hypertrophy observed in Klotho-deficient CKD mice. Circulating levels of the cleaved soluble ectodomain of Klotho were lower in wild-type CKD mice than in control mice and even lower in Klotho-deficient CKD mice. Intravenous delivery of a transgene encoding soluble Klotho ameliorated cardiac hypertrophy in Klotho-deficient CKD mice. These results suggest that the decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate, opening new avenues for treatment of this disease.
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Joonho
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Division of Nephrology, Department of Medicine.
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: An
authors.affiliation: Department of Pathology, and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Division of Nephrology, Department of Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and Chou-long.huang@utsouthwestern.edu.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D005355:Fibrosis; D005966:Glucuronidase / Q000097:blood*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010710:Phosphates / Q000097:blood*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications*; D012307:Risk Factors; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel
chemical_list: C000717428:Fgf23 protein, mouse; D010710:Phosphates; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: heart failure; renal failure; signaling