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Effect of endogenous glucagon like peptide-1 on NHE3 activity in the renal proximal tubule.

Grant number: 13/02703-9
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2013
Effective date (End): March 31, 2015
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Lívia Xavier Soares Farah
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


Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L-cells and released immediately after nutrient ingestion. Obese and type II diabetic patients display a reduction in the post-absorptive secretion of GLP-1, supporting the use of "incretin-based therapy" for treating patients suffering from diabetes and obesity. Although primarily involved in glucose homeostasis, GLP-1 also induces diuresis and natriuresis when administered in pharmacologic doses both in humans and rodents. Previous studies have demonstrated that the underlying mechanism of renal action of GLP-1 as well as of the agonists of the GLP-1 receptor (GLP-1R), involves increases of renal plasma flow and glomerular filtration rate and a decrease of Na+/H+ exchanger isoform 3 (NHE3)-mediated sodium reabsorption in the renal proximal tubule. On the other hand, recent evidences obtained in our laboratory indicate that the GLP-1R blockade with the antagonist exendin-9 induces anti-diuretic, anti-natriuretic and anti-bicarbonaturic effects. These data suggest that endogenous GLP-1 exerts a tonic effect on renal handling of salt and water. GLP-1 may, therefore, be the peptide that protects the body from sodium excess that can occur during meals by enhancing sodium excretion. This project aims to examine the molecular mechanisms by which the GLP-1R blockade causes a decrease in diuresis and natriuresis in rats. To this end, we will test the hypothesis that blocking the endogenous actions of GLP-1 decreases renal plasma flow and glomerular filtration rate due to an increase of the resistance of the renal vascular bed. Additionally, we will test the hypothesis that the antagonism of GLP-1R, via continuous intravenous infusion of the compound exendin-9, increases NHE3 activity in the renal proximal tubule by inhibiting the cAMP/PKA pathway and by redistributing NHE3 from the intermicrovilar domain to the microvilar domain of the renal proximal tubule. The knowledge gained through this project may provide a better understanding of the underlying mechanisms by which obese and / or type II diabetic patients develop hypertension.

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
FARAH, Lívia Xavier Soares. Effect of endogenous glucagon like peptide-1 on NHE3 activity in the renal proximal tubule. 2015. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.

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