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Effects of dipeptidyl peptidase IV inhibition on renal handling of salt and water in rats with congestive heart failure

Grant number: 14/05714-4
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2014
Effective date (End): May 31, 2016
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Flavia Leticia Martins
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

Studies conducted by numerous research laboratories, including ours, underscore the need for undertaking cardiorenal approaches to effectively contain the progression of certain cardiovascular diseases. Edema is the hallmark of congestive heart failure (HF). The most important causes of edema in HF are salt and water retention by the kidneys. The potential causes of altered renal handling of salt and water may involve a decrease in glomerular filtration rate, an increase in tubular reabsorption of sodium or both. We have previously demonstrated that the enzyme dipeptidyl peptidase IV ( DPPIV) physically associates with the Na+/ H+ exchanger isoform 3 (NHE3) in the renal proximal tubule and that DPPIV inhibitors inhibit the transport activity of this transporter. Additionally, we have demonstrated that the peptide glucagon-like - 1 (GLP- 1) , a well known substrate of DPPIV, which has natriuretic and vasodilatory actions, upon binding to its receptor GLP-1R, activates the cAMP/PKA signaling cascade and consequently inhibits NHE3 activity in renal proximal tubule. Furthermore, GLP-1 increases glomerular filtration rate and renal plasma flow in healthy rats. In the present study, we will test the hypothesis that administration of the DPPIV inhibitor (vildagliptin) restores renal handling of salt and water in rats with congestive HF. More specifically, we will investigate whether: ( i ) the administration of the vildagliptin reduces pulmonary congestion , (ii ) normalizes glomerular filtration rate , increases the levels of phosphorylation of serine 552, a consensus site for PKA located in the tail C -terminal NHE3 in the renal cortex, and reduces the activity of this transporter in rats with established HF.