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

Rios, Francisco J.; Zou, Zhi-Guo; Harvey, Adam P.; Harvey, Katie Y.; Camargo, Livia L.; Neves, Karla B.; 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. (2022): TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt. In: Communications Biology, Vol. 5, No. 1, 746

Abstract

Hyperaldosteronism causes cardiovascular disease as well as hypomagnesemia. Mechanisms are ill-defined but dysregulation of TRPM7, a Mg2+-permeable channel/alpha-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(+/Delta kinase)) mice. Plasma/tissue [Mg2+] and TRPM7 phosphorylation were reduced in vehicle-treated TRPM7(+/Delta kinase) 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(+/Delta kinase) 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(+/Delta kinase) 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. Deficiency of the Mg2+-permeable channel/alpha-kinase TRPM7 in mice increases susceptibility to cardiovascular and renal fibrosis induced by aldosterone and salt.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• Language: English