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Molecular mechanisms of the anti-hypertensive action of incretin mimetics and dipeptidyl peptidase IV inhibitors

Grant number: 12/09036-5
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2012
Effective date (End): February 29, 2016
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Gabriela Cozin Aragão
Home 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

Abstract

The incretin hormone glucagon like peptide-1 (GLP-1) has insulinotropic actions that contribute to the maintenance of the blood glucose levels, and it is therefore considered a potential target for the treatment of type 2 Diabetes (DM2). In an attempt to overcome the limitations to the therapeutic use of GLP-1, the following strategies have been employed: (i) the use of incretin mimetics and (ii) the use of inhibitors of the enzyme responsible for the rapid inactivation of GLP-1, the dipeptidyl peptidase IV (DPPIV). Accumulating evidence from experimental studies and clinical trials suggests that incretin mimetics and DPPIV inhibitors may act as potential antihypertensive agents. The main mechanisms by which these agents induce their blood-pressure-lowering effect appear to be via the inhibition of sodium reabsorption in the renal proximal tubule and/or systemic vasodilation. However, the molecular mechanisms underlying the antihypertensive action of these agents in renal tissue and the vascular bed have not been completely elucidated. Detailed mechanisms of incretin-mediated sodium handling in the kidney as well as its vascular effects merit further study. Additionally, it is known that DPPIV may cleave many other peptides other than incretins. Therefore, DPPIV may also prolong the active half-life of these peptides. Thus, it is of interest to determine whether the antihypertensive effect of the DPPIV inhibitors is solely mediated by GLP-1, or if there are other peptides, substrates for this enzyme, involved in blood pressure control. In light of the above, this project aims to: (1) test the hypothesis that the antihypertensive effects of the incretin mimetics and of the inhibitors of DPPIV are at least partly mediated through inhibition of the type 3 isoform 3 of the Na+/H+ exchanger (NHE3) in the renal proximal tubule, as well as evaluating the molecular mechanisms that mediate this inhibition; (2) test the hypothesis that the antihypertensive effects of the incretin mimetics and of the DPPIV inhibitors are, at least in part, promoted by vasodilation; (3) test the hypothesis that the antihypertensive effect of DPPIV inhibitors are mediated by GLP-1. The knowledge gained through this project may clarify the real benefits of renal and cardiovascular promising incretin-based therapy, currently used in patients at risk for cardiovascular diseases such as diabetic, obese subjects and/or patients with metabolic syndrome. (AU)