Participation of mineralocorticoid receptors on obesity-induced Th17 infiltration, interleukin-17 release and alteration of the anti-contractile phenotype of perivascular adipose tissue

• Grant number: 23/11150-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: January 01, 2024
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Thales de Mileto Henrique Dourado
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 25/00579-6 - Participation of aldosterone in the modulation of TRPM7 channels in perivascular adipose tissue and the implications of Mg2+ deficiency for its anti-contractile effect, BE.EP.DR

Abstract

The prevalence of obesity in Brazil increased from 11.8% in 2006 to 20.3% in 2019. For this reason, this condition is considered a public health problem in Brazil, generating expenses of over R$ 1 billion annually. Obesity is a risk factor for the development of cardiovascular diseases, including high blood pressure. Obesity promotes functional and structural alterations in the vasculature, in addition to affecting the perivascular adipose tissue (PVAT), a biologically active tissue composed of adipocytes, capillaries and immune and inflammatory cells, which displays anticontractile action under physiological conditions. Obesity alters PVAT phenotype favoring a pro-oxidative and pro-inflammatory phenotype, which is characterized by increased production of reactive oxygen species (ROS), decreased bioavailability of nitric oxide (NO), leukocyte infiltration and release of pro-inflammatory cytokines and chemokines. Furthermore, during obesity there is stimulation of the renin-angiotensin-aldosterone system (RAAS), which is responsible for secondary hypertension in obese individuals. The activation of mineralocorticoid receptors (MR) by aldosterone stimulates pro-inflammatory pathways that favor the development of cardiovascular diseases. Activation of MR induces polarization of naive lymphocytes to the Th17 phenotype, in addition to increasing the production of IL-17, an interleukin that has important pathophysiological actions that contribute to cardiovascular changes during obesity. For example, IL-17 favors the production of ROS and reduces the bioavailability of NO. However, the relationship between MR, Th17 lymphocyte infiltration, IL-17 release and loss of the anti-contractile effect of PVAT during obesity remains elusive. The hypothesis of the present study is that obesity will stimulate the RAAS, with further increase in aldoserore, which will activate MR leading to polarization of naive T lymphocytes towards the Th17 phenotype. The latter will infiltrate in PVAT and release IL-17, which will ultimately increase ROS generation, reduce NO bioavailability, leading to loss of the anti-contractile effect of PVAT (marker of PVAT dysfunction). This study aims to fill a gap in the mechanism that leads to the inflammatory state in obesity, focusing on PVAT, which has been establishing itself as an important therapeutic target due to its importance in the vascular system. With this purpose, male C57Bl6 mice will be fed a hypercaloric diet (12 weeks) to induce obesity. The participation of MR in lymphocyte polarization will be evaluated using potassium canrenoate (MR antagonist) for 4 weeks. The participation of IL-17 will be evaluated using knockout animals for the IL-17 receptor (B6.Cg-Il17ratm2.2Koll/J). Functional (blood pressure, vascular reactivity) and molecular (flow cytometry, ELISA, immunofluorescence...) experiments will be performed using the PVAT that surrounds the mesenteric arterial bed.