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

Author

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  • Jian Xie

    (UT Southwestern Medical Center)

  • Seung-Kuy Cha

    (UT Southwestern Medical Center
    Present address: Department of Physiology and Institute of Life Style Medicine, Yonsei University Wonju College of Medicine, Ilsan-Dong 162, Wonju, Kangwondo 220-701, Republic of Korea)

  • 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)

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.

Suggested Citation

  • Jian Xie & Seung-Kuy Cha & Sung-Wan An & Makoto Kuro-o & Lutz Birnbaumer & Chou-Long Huang, 2012. "Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2240
    DOI: 10.1038/ncomms2240
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    Cited by:

    1. Ji-Hee Kim & Kyu-Hee Hwang & Bao T. N. Dang & Minseob Eom & In Deok Kong & Yousang Gwack & Seyoung Yu & Heon Yung Gee & Lutz Birnbaumer & Kyu-Sang Park & Seung-Kuy Cha, 2021. "Insulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Sayaka Oda & Kazuhiro Nishiyama & Yuka Furumoto & Yohei Yamaguchi & Akiyuki Nishimura & Xiaokang Tang & Yuri Kato & Takuro Numaga-Tomita & Toshiyuki Kaneko & Supachoke Mangmool & Takuya Kuroda & Reish, 2022. "Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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