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Here, we demonstrate a critical role of the exchange protein directly activated by cAMP (Epac) signaling, and particularly the Epac2, in governing renal adaptation to dietary acid load. RNAseq analysis of the renal cortical area revealed that Epac1&amp;2 deficiency was associated with changes in gene profile seen in acidosis. Renal expression of Epac2 but not Epac1 was enhanced by acid load. Epac2-\/- mice developed a pronounced metabolic acidosis due to the inability to acidify urine in response to dietary acid load. Deletion of Epac2 and Epac1 exerted additive inhibitory actions on expression of the Na+\/H+ exchanger (NHE-3, Slc9a3) in the proximal tubule. Using super-resolution STED microscopy, we detected NHE-3 redistribution to the base of the brush border, which led to the impaired recovery after acidification in freshly isolated split-opened proximal tubules from Epac1&amp;2-\/- mice. Deletion of Epac2 but not Epac1 diminished H+ secretion in freshly isolated split-opened collecting ducts, compromised apical translocation of V-ATPase, and reduced anion exchanger 1 (AE1, Slc4a1) expression in the A-type intercalated cells, and caused lower levels of titratable acids in urine, whereas ammoniagenesis was not compromised. Overall, we demonstrate a previously unrecognized role of Epac signaling in renal adaptation to dietary acidification. While both Epac1 and Epac2 isoforms control NHE-3-dependent H+ secretion in the proximal tubule, only Epac2 is essential to augment H+ transport in the collecting duct to acidify urine.<\/jats:p>","DOI":"10.1093\/function\/zqaf048","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T11:52:51Z","timestamp":1760356371000},"source":"Crossref","is-referenced-by-count":2,"title":["Epac2 Deficiency Compromises Adaptation to Dietary Acidification by Decreasing H+ Transport in the Renal Nephron"],"prefix":"10.1152","volume":"6","author":[{"given":"Kyrylo","family":"Pyrshev","sequence":"first","affiliation":[{"name":"The University of Texas Health Science Center at Houston Department of Integrative Biology and Pharmacology, , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Atamanchuk","sequence":"additional","affiliation":[{"name":"The University of Texas Health Science Center at Houston 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