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Role of proximal tubule dipeptidyl peptidase 4 in angiotensin II-induced hypertension

Grant number: 22/12282-0
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): January 01, 2023
Effective date (End): December 31, 2023
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Adriana Castello Costa Girardi
Grantee:Flavia Leticia Martins
Supervisor: Ravi Nistala
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
Research place: University of Missouri, Columbia (UM), United States  
Associated to the scholarship:19/11944-6 - Interaction between dipeptidyl peptidase IV and the intra-renal renin angiotensin system on blood pressure levels and sodium transport throughout the nephron, BP.DR


Dipeptidyl peptidase 4 (DPP4) inhibitors are antidiabetic agents that exert renoprotective effects beyond glucose control in humans and experimental models of cardiovascular and renal diseases. DPP4 inhibition reduces Na+/H+ exchanger isoform 3 (NHE3)-dependent sodium reabsorption in the renal proximal tubule, and this inhibitory effect is associated with blood pressure lowering effects in experimental hypertension. Angiotensin II (Ang II) is a very potent vasoconstrictor and an important mediator of sodium and water retention by the kidneys. One of the mechanisms by which Ang II exerts its renal actions is through proximal tubule NHE3 activation. Recent reports have demonstrated the existence of a crosstalk between DPP4 and the renin-angiotensin system (RAS) activation. More specifically, studies from the Nistala lab have shown that supraphysiological concentrations of Ang II, the main effector of RAS, increases DPP4 activity in the renal proximal tubule in vivo and in vitro. Furthermore, studies from the Girardi lab provide evidence of a positive correlation between DPP4 activity and Ang II concentration in experimental models of cardiovascular and renal diseases, including chronic kidney disease and heart failure. However, little is known about how the interplay between DPP4 and Ang II on the renal tubule affects sodium handling and blood pressure. Therefore, this study aims to test the hypothesis that selective deletion of DPP4 on the proximal tubule attenuates blood pressure rising in response to Ang II in male and female mice, at least partly due to the downregulation of NHE3 in the renal proximal tubule. Moreover, we intend to elucidate the signaling mechanisms mediating the interplay between proximal tubule DPP4 and RAS activation. (AU)

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