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Role of endogenous GLP-1 in protecting against salt-sensitive hypertension

Grant number: 23/03620-1
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): May 01, 2023
Effective date (End): April 30, 2027
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Gabriela Catão Diniz Braga
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

A series of clinical and experimental evidence documents the importance of the kidneys in the pathogenesis of arterial hypertension. The extracellular volume and sodium ion balance are maintained through the regulation of a series of sodium transporters expressed in the apical membrane of the renal tubule. Consequently, changes in these transporters' number and/or intrinsic activity affect sodium reabsorption, extracellular volume, and blood pressure. Our research group pioneered in demonstrating that endogenous glucagon-like peptide-1 (GLP-1) exerts actions on the kidney. We found that acute blockade of the endogenous GLP-1 receptor (GLP-1R) signaling induces anti-natriuretic and antidiuretic effects, at least in part, by "disinhibiting" NHE3 via serine 552 phosphorylation. In line with these findings, long-term blockade of endogenous GLP-1R signaling increases blood pressure levels in normotensive and hypertensive rats, impairs salt and water handling by the kidneys, increases NHE3-dependent salt reabsorption, as well as activates the intrarenal renin-angiotensin system. These data suggest that GLP-1 may be a peptide that protects the body from excess sodium ingested during meals by providing increased urinary excretion of this ion.Given the above, this project aims to test the hypothesis that endogenous GLP-1 protects against salt sensitivity and investigate the underlying mechanisms. For this purpose, 2-month-old male Wistar rats will be treated with a GLP-1R antagonist (exendin-9) and fed a high-sodium (HS), normal, and low-sodium (LS) diet. Vehicle-treated Wistar rats fed these same diets will be used as controls. We expect that renal and vascular compensatory mechanisms prevent the increase in blood pressure levels in vehicle-treated Wistar rats fed the HS diet (salt-resistant model). In turn, in Wistar treated with exendin-9, we postulate that the increase in blood pressure promoted by the blockade of GLP-1R will be intensified by the HS diet and attenuated by the LS diet (salt-sensitive model). From the point of view of mechanisms, we will evaluate the prolonged effects of GLP-1R blockade and salt consumption on protein expression, phosphorylation levels, or cleavage of sodium transporters in the apical membrane of renal tubule cells. Given the pharmacological effects of GLP-1 agonists on the renin-angiotensin system, sympathetic nervous system, and immune system, we will investigate whether endogenous GLP-1R blockade interferes with the intrarenal activation of these systems, considering the influence of salt intake. (AU)

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