Impact of Proximal Tubule-Specific Deletion of Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and NHE3 Phosphorylation

Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase abundantly expressed in the kidneys, predominantly in the proximal tubule (PT); however, its non-enzymatic functions in this nephron segment remain poorly understood. While DPP4 physically associates with the Na+/H+ exchanger isoform 3 (NHE3) and its inhibitors exert natriuretic effects, the DPP4 role in blood pressure (BP) regulation remains controversial. This study investigated the effects of PT-specific Dpp4 deletion (Dpp4{Delta}PT) and global Dpp4 deletion (Dpp4-/-) on systolic blood pressure (SBP), natriuresis, and NHE3 regulation under baseline and angiotensin II (Ang II)-stimulated conditions in both male and female mice. Global and PT-specific Dpp4 deletion increased diuretic and natriuretic responses to acute saline loading, correlating with enhanced phosphorylation of NHE3 at serine 552 (pS552-NHE3). However, baseline SBP remained unchanged. Ang II stimulation increased DPP4 activity in control mice, with a greater effect in males than in females, reflecting sex-dependent regulation of renal DPP4. In Dpp4{Delta}PT mice, residual kidney DPP4 was unresponsive to Ang II, indicating that PT DPP4, rather than DPP4 in other nephron segments, is regulated by Ang II. Ang II administration increased SBP in all groups; however, the pressor response was significantly attenuated in both Dpp4{Delta}PT and Dpp4-/- mice, coinciding with sustained elevated levels of pS552-NHE3. Collectively, these findings demonstrate that PT DPP4 modulates NHE3 activity through mechanisms that prevent the accumulation of pS552-NHE3, exerting an anti-natriuretic effect. In the absence of DPP4, these mechanisms are disrupted, reducing Ang II sensitivity and maintaining high pS552-NHE3 levels, underscoring the role of DPP4 in PT signaling and function.