Klotho and phosphate are modulators of pathologic uremic cardiac remodeling

Ming Chang Hu*, Mingjun Shi, Han Jun Cho, Beverley Adams-Huet, Jean Paek, Kathy Hill, John Shelton, Ansel P. Amaral, Christian Faul, Masatomo Taniguchi, Myles Wolf, Markus Brand, Masaya Takahashi, Makoto Kuro-o, Joseph A. Hill, Orson W. Moe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

213 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1290-1302
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number6
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Medicine(all)


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