Evaluation of the Effect of Steroidal and Nonsteroidal Mineralocorticoid Receptor Antagonists on Perivascular Adipose Tissue Dysfunction in Renovascular Hypertension

• Grant number: 24/19952-6
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luciana Venturini Rossoni
• Grantee: Patrizia Dardi
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/02092-4 - Evaluation of the Effect of Steroidal and Nonsteroidal Mineralocorticoid Receptor Antagonists on Perivascular Adipose Tissue Dysfunction in Renovascular Hypertension, AP.R

Abstract

Renovascular hypertension is the main cause of secondary hypertension, which correlates with obstruction of the renal arteries and progressive reduction in renal perfusion, leading to chronic and sustained activation of the renin-angiotensin-aldosterone system. Aldosterone is considered an important therapeutic target in hypertension, and its effects are mediated by the activation of the mineralocorticoid receptor (MR). MR antagonists are commonly recommended for treating hypertension, mainly due to their natriuretic and potassium-sparing action. This class of drugs is comprised of steroidal antagonists, such as spironolactone and eplerenone, and non-steroidal antagonists, such as finerenone and esaxerenone. In addition to the greater selectivity of action in the MR, finerenone does not cross the blood-brain barrier and is not detected in the brain. Therefore, comparing the effect of these two classes of drugs becomes important to differentiate the peripheral and central components of MR action. Initially described to be expressed only in the kidney, MR is known to have an extensive extra-renal distribution, including in the brain, heart, vasculature, and more recently, in adipose tissue, such as perivascular adipose tissue (PVAT). PVAT is closely associated with the cardiovascular system, as it secretes several vasoactive substances that influence vascular homeostasis. Under physiological conditions, PVAT is known for its anti-contractile effect by secreting vasodilatory substances, such as adiponectin, which are regulated by activating ²3-adrenergic receptors (AR). Preliminary results from our group, obtained in mesenteric resistance arteries of mice subjected to two-kidney, one-clip renovascular hypertension (2K1C), demonstrate the loss of the anticontractile effect of PVAT, but the mechanisms are not yet elucidated. It is known that MR activation increases sympathetic activity, and that hyperactivation of ²-AR and MR can result in PVAT dysfunction; therefore, we hypothesize that both mechanisms may be involved in PVAT dysfunction in 2K1C hypertension. Therefore, this project aims to investigate whether MR hyperactivation in perivascular adipocytes participates in PVAT dysfunction and whether it is amplified by a central effect of MR activation via the sympathetic nervous system, leading to a pro-oxidative, inflammatory, and fibrotic condition of the PVAT and their mesenteric resistance arteries, increasing peripheral vascular resistance and worsening renovascular hypertension.