1. TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt
- Author
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Francisco J. Rios, Zhi-Guo Zou, Adam P. Harvey, Katie Y. Harvey, Livia L. Camargo, Karla B. Neves, Sarah E. F. Nichol, Rheure Alves-Lopes, Alexius Cheah, Maram Zahraa, Alexey G. Ryazanov, Lillia Ryazanova, Thomas Gudermann, Vladimir Chubanov, Augusto C. Montezano, and Rhian M. Touyz
- Subjects
Protein Phosphatase 2C ,Mice ,Hyperaldosteronism ,Animals ,TRPM Cation Channels ,Medicine (miscellaneous) ,Magnesium ,Sodium Chloride ,Kidney ,General Agricultural and Biological Sciences ,Aldosterone ,Fibrosis ,General Biochemistry, Genetics and Molecular Biology - 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.
- Published
- 2022