Participation of aldosterone in the modulation of TRPM7 channels in perivascular adipose tissue and the implications of Mg2+ deficiency for its anti-contractile effect

• Grant number: 25/00579-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Thales de Mileto Henrique Dourado
• Supervisor: Rhian Merry Touyz
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: McGill University, Montreal, Canada
• Associated to the scholarship: 23/11150-5 - Participation of mineralocorticoid receptors on obesity-induced Th17 infiltration, interleukin-17 release and alteration of the anti-contractile phenotype of perivascular adipose tissue, BP.DR

Abstract

Aldosterone is the terminal hormone of the renin-angiotensin-aldosterone system (RAAS) that displays important actions on electrolyte balance and volume control. However, in pathophysiological conditions, aldosterone production can be increased, and activation of the mineralocorticoid receptor (MR) can cause dysfunction and damage to different tissues. In the cardiovascular system, aldosterone increases the production of reactive oxygen species (ROS), promotes inflammation, and fibrosis. One of the mechanisms through which aldosterone promotes deleterious effects in the cardiovascular system is by negatively modulating the Ca2+/Mg2+/Zn2+-permeable non-selective cation channel TRPM7. In the cardiovascular system, TRPM7 has a protective effect, and the deficiency of this channel leads to inflammatory responses and oxidative damage. One of the consequences of TRPM7 deficiency is hypomagnesemia, which is associated with increased circulating aldosterone. Perivascular adipose tissue (PVAT) is an important modulator of vascular function, and functional and biochemical changes in this tissue lead to vascular dysfunction, Thus, we hypothesized that aldosterone will reduce the TRPM7-Mg2+ axis in adipocytes from mesenteric PVAT via MR activation, leading to inflammation, oxidative stress, loss of anticontractile functions, and vascular dysfunction. To test this hypothesis, male C57BL/6 mice will be infused with aldosterone (600 µg/Kg/day) for 4 weeks, and their mesenteric PVAT and plasma will be collected for functional and biochemical assessments. Additionally, mice heterozygous for the deletion of the TRPM7-kinase (TRPM7+/¿kinase) will be used to evaluate the direct effects of TRPM7 deficiency on PVAT (dys)function. In vitro studies using pre-adipocyte cell lines and primary cultures will be carried out to understand the mechanisms through which aldosterone modulates TRPM7 in adipocytes, the biochemical consequences, and the importance of this cation channel in adipocyte function.