Impairment of postprandial GLP-1 bioavailability and renal GLP-1R activation in experimental hypertension: role of salt consumption

• Grant number: 22/15827-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2023
• End date: July 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Victória Cavalcante Sousa
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control, AP.TEM

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells whose primary function involves the maintenance of glycemic homeostasis. However, different studies have consistently demonstrated that GLP-1 receptor (GLP-1R) agonists, drugs used to treat type 2 diabetes mellitus, exert several extraglycemic effects, including increased diuresis and natriuresis and reduced blood pressure (BP) in non-diabetic hypertensive models and patients. Additionally, it has been demonstrated that the acute blockade of GLP-1R through the systemic infusion of the antagonist exendin-9 exerts antinatriuretic and antidiuretic effects in rats. Accordingly, the long-term blockade of this receptor raises blood pressure levels in normotensive and hypertensive rats. Based on these observations, we postulated that GLP-1 might also protect against excessive salt ingested in the diet and that the postprandial levels of this incretin would be reduced in hypertensive individuals, resulting in less activation of the GLP-1R located in the kidneys, increasing fluid and sodium retention, thus contributing in increased BP. Therefore, this project aims to test the hypothesis that the postprandial GLP-1 bioavailability is impaired, renal GLP-1R activation is reduced in hypertension, and salt consumption aggravates this pathophysiological process. To this end, spontaneously hypertensive and normotensive male rats will receive diets containing low, average, and high sodium concentrations for one month. For the analysis of gene and protein expression of GLP-1R, pro-convertase-1/3, and pro-glucagon, kidneys and intestines will be collected for quantitative PCR and immunoblotting assays. For evaluation of intact, total GLP-1 and insulin, blood will be collected under fasting and postprandial conditions. Additionally, urine will be collected for cAMP analysis. The results obtained through this project may provide a better understanding of salt sensitivity mechanisms and the role of GLP-1 in the pathophysiology of arterial hypertension.