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 and Chou-Long Huang ()
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Jian Xie: UT Southwestern Medical Center
Seung-Kuy Cha: UT Southwestern Medical Center
Sung-Wan An: UT Southwestern Medical Center
Makoto Kuro-o: UT Southwestern Medical Center
Lutz Birnbaumer: Laboratory of Neurobiology, National Institute of Environmental Health Sciences
Chou-Long Huang: UT Southwestern Medical Center

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/ncomms2240

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