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Interplay between dipeptidyl peptidase-4 and Angiotensin II on renal proximal tubule NHE3-mediated sodium reabsorption and blood pressure regulation


Dipeptidyl peptidase 4 (DPP4) inhibitors are antidiabetic agents that exert renoprotective effects, beyond glucose control in humans and in 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 hypertensive and/or animals with kidney disease. 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 raised the intriguing possibility of crosstalk between DPP4 and the renin-angiotensin system (RAS) activation in cardiorenal physiology and pathophysiology. More specifically, studies from the Nistala lab have demonstrated that Ang II, the main effector of RAS, increases DPP4 activity in the renal proximal tubule both in vivo and in vitro. Furthermore, studies from the Girardi lab provide evidence that there is a positive correlation between DPP4 activity and Ang II concentration in the heart and kidneys of rats with experimental chronic kidney disease. However, little is known about the potential interplay between DPP4 and Ang II on renal tubule sodium handling and blood pressure. Therefore, we hypothesize that Ang II activation of DPP4 leads to regulation of renal sodium handling via NHE3. This project aims to test the hypothesis via the following Specific Aims: 1) Investigate the underlying molecular mechanisms of DPP4 inhibition mediated suppression of Ang II activation of NHE3 in the renal proximal tubule both in vivo and in vitro conditions; 2) Examine the mitigating effects of proximal tubule specific knockout of DPP4 in blood pressure rise in response to Ang II in male and female mice. (AU)