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

doi:10.1038/ncomms2240

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

Journal article

Open access

Peer reviewed

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

Nature communications, Vol.3(1), pp.1238-1238

2012

DOI: 10.1038/ncomms2240

PMCID: PMC3526952

PMID: 23212367

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https://doi.org/10.1038/ncomms2240View

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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.

Heart - physiopathology

Down-Regulation

Heart - physiology

Cardiomegaly - physiopathology

Male

Ventricular Remodeling - physiology

Mice, Knockout

Cardiomyopathies - physiopathology

Glucuronidase - physiology

Animals

Myocytes, Cardiac - physiology

Mice

TRPC Cation Channels - physiology

Details

Title: Subtitle: Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
Creators: Jian Xie - Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA
Seung-Kuy Cha
Sung-Wan An
Makoto Kuro-O
Lutz Birnbaumer
Chou-Long Huang
Resource Type: Journal article
Publication Details: Nature communications, Vol.3(1), pp.1238-1238
DOI: 10.1038/ncomms2240
PMID: 23212367
PMCID: PMC3526952
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: Z01 ES101684-06 / Intramural NIH HHS Z01 ES101684-05 / Intramural NIH HHS ZO1-ES-101684 / NIEHS NIH HHS Z01 ES101684 / Intramural NIH HHS R01 DK059530 / NIDDK NIH HHS DK59530 / NIDDK NIH HHS DK79328 / NIDDK NIH HHS P30 DK079328 / NIDDK NIH HHS R01 DK091392 / NIDDK NIH HHS R01 DK085726 / NIDDK NIH HHS DK91392 / NIDDK NIH HHS DK85726 / NIDDK NIH HHS
Language: English
Date published: 2012
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984094544802771

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