Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate

Jian Xie; Joonho Yoon; Sung-Wan An; Makoto Kuro-o; Chou-Long Huang

doi:10.1681/ASN.2014040325

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Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate

Journal article

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Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate

Jian Xie, Joonho Yoon, Sung-Wan An, Makoto Kuro-o and Chou-Long Huang

Journal of the American Society of Nephrology, Vol.26(5), pp.1150-1160

05/2015

DOI: 10.1681/ASN.2014040325

PMCID: PMC4413766

PMID: 25475745

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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.

Cardiomyopathies - blood

Risk Factors

Cardiomyopathies - pathology

Male

Myocardium - pathology

Glucuronidase - blood

Renal Insufficiency, Chronic - complications

Cardiomyopathies - etiology

Renal Insufficiency, Chronic - blood

Animals

Fibroblast Growth Factors - blood

Myocardium - metabolism

Fibrosis

TRPC Cation Channels - metabolism

Phosphates - blood

Mice

Disease Models, Animal

Details

Title: Subtitle: Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate
Creators: Jian Xie - Division of Nephrology, Department of Medicine
Joonho Yoon - Division of Nephrology, Department of Medicine
Sung-Wan An - Division of Nephrology, Department of Medicine
Makoto Kuro-o - 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
Chou-Long Huang - 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
Resource Type: Journal article
Publication Details: Journal of the American Society of Nephrology, Vol.26(5), pp.1150-1160
DOI: 10.1681/ASN.2014040325
PMID: 25475745
PMCID: PMC4413766
NLM abbreviation: J Am Soc Nephrol
ISSN: 1046-6673
eISSN: 1533-3450
Grant note: P30 DK079328 / NIDDK NIH HHS R01 DK085726 / NIDDK NIH HHS R01-DK100605 / NIDDK NIH HHS R01 DK100605 / NIDDK NIH HHS R01-DK85726 / NIDDK NIH HHS P30-DK79328 / NIDDK NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984094554402771

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