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While its enzymatic role is well characterized, its non\u2010enzymatic functions remain unclear. DPP4 physically associates with the Na\n                      <jats:sup>+<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      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\u2013natriuresis by preventing NHE3 phosphorylation at serine 552 (pS552).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated PT\u2010specific\n                      <jats:italic>Dpp4<\/jats:italic>\n                      knockout mice (\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u0394PT<\/jats:sup>\n                      ) and examined the effects of PT\u2010specific and global\n                      <jats:italic>Dpp4<\/jats:italic>\n                      deletion (\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) on systolic blood pressure (SBP), natriuresis, and NHE3 phosphorylation at baseline and following acute angiotensin II (Ang II) infusion in male and female mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u0394PT<\/jats:sup>\n                      and\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      showed enhanced diuretic and natriuretic responses to saline loading, with higher renal pS552\u2010NHE3, and unchanged baseline SBP. Ang II elevated DPP4 activity in controls but not in\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u0394PT<\/jats:sup>\n                      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\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u0394PT<\/jats:sup>\n                      and\n                      <jats:italic>Dpp4<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, paralleling sustained pS552\u2010NHE3 elevation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that DPP4 modulates NHE3 activity by preventing pS552\u2010NHE3 accumulation, promoting an anti\u2010natriuretic effect. In the absence of PT DPP4, these mechanisms are disrupted, reducing Ang II sensitivity, maintaining high pS552\u2010NHE3 levels, and likely enhancing pressure\u2013natriuresis, underscoring the role of PT DPP4 in modulating signaling mechanisms governing renal function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70127","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:51:46Z","timestamp":1762303906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unique Role of Proximal Tubule Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and Na\n                    <sup>+<\/sup>\n                    \/H\n                    <sup>+<\/sup>\n                    Exchanger Isoform 3 Phosphorylation"],"prefix":"10.1111","volume":"241","author":[{"given":"Flavia L.","family":"Martins","sequence":"first","affiliation":[{"name":"Departamento de Cardiopneumologia, Faculdade de Medicina Universidade de S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Division of Nephrology, Department of Medicine University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao Carlos","family":"Ribeiro\u2010Silva","sequence":"additional","affiliation":[{"name":"State University of New York (SUNY) Upstate Medical University  Syracuse New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika Fernandes","family":"de Jesus","sequence":"additional","affiliation":[{"name":"Departamento de Cardiopneumologia, Faculdade de Medicina Universidade de S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Nistala","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine University of Missouri School of Medicine  Columbia Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-6917","authenticated-orcid":false,"given":"Adriana C. 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