Deletion of dipeptidyl peptidase 4 attenuates angiotensin II-induced blood pressure rise and enhances NHE3 phosphorylation at serine 552 in the kidneys of male and female mice

Abstract

Dipeptidyl peptidase 4 (DPP4) physically associates with the Na+/H+ exchanger isoform3 (NHE3), and DPP4 inhibitors reduce NHE3-dependent sodium reabsorption in the renal proximal tubule. Angiotensin II (Ang II) is a key mediator of sodium and water retention by the kidneys, partly through the activation of proximal tubule NHE3. Recent studies from our group reveled that Ang II activates DPP4 by, both in vivo and in vitro, and that inhibition of several canonical and non-canonical pathways can suppress this activation. However, the impact of this interaction on renal sodium handling and blood pressure remains unclear. This study aimed to test the hypothesis that DPP4 deletion mitigates the blood pressure elevation induced by Ang II in male and female mice, at least partly due to the downregulation of NHE3 in the renal proximal tubule. Male and female mice with global DPP4 deletion or wild-type controls were acutely administered either a pressor dose of Ang II (1000 ng/kg/minute) or saline. Blood pressure was measured before and one hour after the administration of Ang II or saline by tail-cuff plethysmography. Kidneys were subsequently collected for protein homogenate preparation. Increased DPP4 activity was observed in response to acute Ang II stimulation in both male and female wild-type mice, with female mice exhibiting higher basal DPP4 activity. As expected, DPP4 knockout mice exhibited minimal DPP4 activity. Baseline blood pressure did not differ significantly between male wild-type and DPP4 knockout mice or between females. In line with our hypothesis, both male and female DPP4 knockout mice displayed a reduced increase in blood pressure in response to acute Ang II administration compared to their wild-type counterparts. Furthermore, the phosphorylation of NHE3 at serine 552 (pS552-NHE3), a surrogate marker of NHE3 inhibition, was higher in wild-type females than males. Interestingly, pS552-NHE3 was fivefold higher in male DPP4 knockout mice and threefold higher in female DPP4 knockout mice compared to their wild-type counterparts. Additionally, the increase in pS552-NHE3 one hour after Ang II administration was higher in males (1208 ± 119 vs. 544 ± 54 %, P < 0.01) and females (385 ± 18 vs. 271 ± 27%, P < 0.01) DPP4 knockout mice compared to wild-type animals. Moreover, ERK, a well-known effector of the AT1R signaling cascade, was phosphorylated in a similar manner as NHE3 in response to Ang II in males but not in females. In conclusion, our data demonstrate that the absence of DPP4 reduces the rise in blood pressure induced by acute Ang II stimulation, possibly through Ang II/AT1R signaling pathways influencing phosphorylation of downstream effectors such as NHE3. Furthermore, we observe significant sex differences in Ang II effects on DPP4 activity, and AT1R signaling cascades. FAPESP 2021/14524-3 NIDDKD - K08DK115886. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.