Unique Role of Proximal Tubule Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and Na(+)/H(+) Exchanger Isoform 3 Phosphorylation.

BACKGROUND: Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase highly expressed in the proximal tubule (PT). While its enzymatic role is well characterized, its non-enzymatic functions remain unclear. DPP4 physically associates with the Na(+)/H(+) exchanger isoform 3 (NHE3), and DPP4 inhibitors promote natriuresis; however, the mechanisms by which DPP4 regulates NHE3 and its role in blood pressure (BP) regulation remain controversial. We hypothesized that PT DPP4 promotes sodium reabsorption and attenuates pressure-natriuresis by preventing NHE3 phosphorylation at serine 552 (pS552). METHODS: We generated PT-specific Dpp4 knockout mice (Dpp4(ΔPT)) and examined the effects of PT-specific and global Dpp4 deletion (Dpp4(-/-)) on systolic blood pressure (SBP), natriuresis, and NHE3 phosphorylation at baseline and following acute angiotensin II (Ang II) infusion in male and female mice. RESULTS: Both Dpp4(ΔPT) and Dpp4(-/-) showed enhanced diuretic and natriuretic responses to saline loading, with higher renal pS552-NHE3, and unchanged baseline SBP. Ang II elevated DPP4 activity in controls but not in Dpp4(ΔPT) mice, suggesting that PT DPP4, rather than DPP4 in other nephron segments, is regulated by Ang II under these experimental conditions. Ang II increased SBP in all groups, but the pressor response was significantly attenuated in both Dpp4(ΔPT) and Dpp4(-/-) mice, paralleling sustained pS552-NHE3 elevation. CONCLUSION: These findings demonstrate that DPP4 modulates NHE3 activity by preventing pS552-NHE3 accumulation, promoting an anti-natriuretic effect. In the absence of PT DPP4, these mechanisms are disrupted, reducing Ang II sensitivity, maintaining high pS552-NHE3 levels, and likely enhancing pressure-natriuresis, underscoring the role of PT DPP4 in modulating signaling mechanisms governing renal function.