TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt

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Rios, Francisco J. and Zou, Zhi Guo and Harvey, Adam P. and Harvey, Katie Y. and Camargo, Livia L. and Neves, Karla B. and Nichol, Sarah E.F. and Alves-Lopes, Rheure and Cheah, Alexius and Zahraa, Maram and Ryazanov, Alexey G. and Ryazanova, Lillia and Gudermann, Thomas and Chubanov, Vladimir and Montezano, Augusto C. and Touyz, Rhian M. (2022) TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt. Communications Biology, 5 (1). 746. ISSN 2399-3642 (https://doi.org/10.1038/s42003-022-03715-z)

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Abstract

Hyperaldosteronism causes cardiovascular disease as well as hypomagnesemia. Mechanisms are ill-defined but dysregulation of TRPM7, a Mg2+-permeable channel/α-kinase, may be important. We examined the role of TRPM7 in aldosterone-dependent cardiovascular and renal injury by studying aldosterone-salt treated TRPM7-deficient (TRPM7+/Δkinase) mice. Plasma/tissue [Mg2+] and TRPM7 phosphorylation were reduced in vehicle-treated TRPM7+/Δkinase mice, effects recapitulated in aldosterone-salt-treated wild-type mice. Aldosterone-salt treatment exaggerated vascular dysfunction and amplified cardiovascular and renal fibrosis, with associated increased blood pressure in TRPM7+/Δkinase mice. Tissue expression of Mg2+-regulated phosphatases (PPM1A, PTEN) was downregulated and phosphorylation of Smad3, ERK1/2, and Stat1 was upregulated in aldosterone-salt TRPM7-deficient mice. Aldosterone-induced phosphorylation of pro-fibrotic signaling was increased in TRPM7+/Δkinase fibroblasts, effects ameliorated by Mg2+ supplementation. TRPM7 deficiency amplifies aldosterone-salt-induced cardiovascular remodeling and damage. We identify TRPM7 downregulation and associated hypomagnesemia as putative molecular mechanisms underlying deleterious cardiovascular and renal effects of hyperaldosteronism.

ORCID iDs

Rios, Francisco J., Zou, Zhi Guo, Harvey, Adam P., Harvey, Katie Y., Camargo, Livia L., Neves, Karla B. ORCID logoORCID: https://orcid.org/0000-0001-5158-9263, Nichol, Sarah E.F., Alves-Lopes, Rheure, Cheah, Alexius, Zahraa, Maram, Ryazanov, Alexey G., Ryazanova, Lillia, Gudermann, Thomas, Chubanov, Vladimir, Montezano, Augusto C. and Touyz, Rhian M.;
CORE (COnnecting REpositories)