Interaction between dipeptidyl peptidase IV and the intra-renal renin angiotensin system on blood pressure levels and sodium transport throughout the nephron

• Grant number: 19/11944-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2020
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Flavia Leticia Martins
• 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: 16/22140-7 - Molecular bases of renal tubular function and dysfunction, AP.TEM
• Associated scholarship(s): 22/12282-0 - Role of proximal tubule dipeptidyl peptidase 4 in angiotensin II-induced hypertension, BE.EP.DR

Abstract

Inhibitors of the enzyme dipeptidyl peptidase IV (DPPIV) are antidiabetic agents which exert renoprotective effects, beyond the glycemic benefit, in humans and experimental models of cardiovascular and renal diseases. Inhibition of DPPIV reduces Na+/H+ exchanger 3 (NHE3)-dependent Na+ reabsorption in proximal renal tubule and this inhibitory effect is associated with the reduction of blood pressure in arterial hypertension and Chronic Kidney Disease (CKD) models. Angiotensin II (Ang II) is a potent vasoconstrictor and important mediator of Na+/water renal retention in proximal tubule, and one of the mechanisms by which this occurs is by the activation of NHE3. Recent data suggest the existence of a crosstalk between DPPIV and Ang II. Specifically, Ang II has been shown to increase the activity of DPPIV in the renal proximal tubule both in vivo and in vitro. Additionally, it has been found that there is a positive correlation between DPPIV activity and Ang II concentration in cardiac tissue in CKD rats. However, the possible interaction between DPPIV and Ang II remain unclear, especially regarding Na+ management by renal tubule and effects on blood pressure. In view of the above, this project intends to test the hypotheses that: 1) inhibition of DPPIV opposes to the stimulation of NHE3 in renal proximal tubule promoted by Ang II in vitro and in vivo and to investigate the underlying molecular mechanisms; 2) inhibition of DPPIV attenuates the activation of intrarenal RAS in experimental models of arterial hypertension; 3) inhibition of DPPIV opposes the stimulatory effects of Ang II on Na+ transport throughout the nephron in normotensive and hypertensive rats. (AU)