Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart

Jian Xie, Seung Kuy Cha, Sung Wan An, Makoto Kuro-O, Lutz Birnbaumer, Chou Long Huang

Research output: Contribution to journalArticlepeer-review

250 Citations (Scopus)


Klotho is a membrane protein predominantly produced in the kidney that exerts some antiageing effects. Ageing is associated with an increased risk of heart failure; whether Klotho is cardioprotective is unknown. Here we show that Klotho-deficient mice have no baseline cardiac abnormalities but develop exaggerated pathological cardiac hypertrophy and remodelling in response to stress. Cardioprotection by Klotho in normal mice is mediated by downregulation of TRPC6 channels in the heart. We demonstrate that deletion of Trpc6 prevents stress-induced exaggerated cardiac remodelling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodelling. Klotho overexpression ameliorates cardiac pathologies in these mice and improves their long-term survival. Soluble Klotho present in the systemic circulation inhibits TRPC6 currents in cardiomyocytes by blocking phosphoinositide-3-kinase-dependent exocytosis of TRPC6 channels. These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.

Original languageEnglish
Article number1238
JournalNature communications
Publication statusPublished - 2012

Bibliographical note

Funding Information:
We thank Eric Olson for TRPC6-Tg mice, Jyothsna Gattineni for assistance with measurements of serum FGF23 and phosphate, Masaya Takahashi and Kim Kangasniemi for cardiac MRI, and Peter Igarashi, Orson Moe and Aylin Rodan for discussions and comments. This work was supported by NIH (DK59530, DK85726, DK79328, DK91392), the Intramural Research Program of the NIH (ZO1-ES-101684) and by a GRIP grant from Genzyme, Inc. C.-L.H. holds the Jacob Lemann Professorship in Calcium Transport of University of Texas Southwestern Medical Center.

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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