Epac2 is critical for regulation of acid-base transport in the renal tubule

Introduction: Kidneys are central in maintaining systemic acid-base homeostasis by recovering filtered bicarbonate (HCO 3 - ) in the proximal tubule (PT) and by secreting H + in A-type intercalated cells (A-ICs) of the collecting duct (CD). Although elevations in cAMP levels have profound actions on renal ion transport, the contribution of specific downstream pathways, such as exchange proteins directly activated by cAMP (Epac1 and Epac2), to acid-base regulation remains unexplored. Guided by our RNAseq analysis of renal cortical tissue, which revealed acidosis-like transcriptional signatures in Epac1&2-deficient mice, we hypothesized that Epac isoforms modulate nephron-specific responses to dietary acid load. Methods: To address this, we combined metabolic cage studies, blood gas analysis, western blotting, functional pH recovery assays in freshly isolated split-opened PT and CD segments, and STED super-resolution microscopy. Mice lacking Epac1, Epac2, or both isoforms were administered regular or acidified water (280 mM NH 4 Cl + 0.5% sucrose) for 3 days, with EpacWT mice serving as control. Results: At baseline, arterial pH, HCO 3 - , and Cl - levels were comparable across genotypes. However, Epac2-/- and Epac1&2-/- mice showed significantly lower urinary pH. Upon acid loading, EpacWT and Epac1-/- mice displayed the expected reduction in arterial pH and a robust decline in urinary pH, whereas Epac2-/- and Epac1&2-/- mice developed a pronounced metabolic acidosis and failed to sufficiently acidify urine. This defect was accompanied by a markedly reduced urinary titratable acid excretion in mice lacking Epac2 or both isoforms, while ammoniagenesis remained intact. In the PT, deletion of either Epac isoform decreased NHE-3 abundance, with the lowest levels observed in Epac1&2-/- mice. Acid loading induced a strong upregulation and apical redistribution of NHE-3 to the brush-border tip in EpacWT and Epac1-/-, but this adaptive response was blunted in Epac2-/- and Epac1&2-/- mice. In the CD, immunofluorescent microscopy revealed markedly reduced AE1 and V-ATPase reporting signals in Epac2-/- and Epac1&2-/- mice. Consistently, Epac2 but not Epac1 was essential for elevation of AE1 expression and apical recruitment of V-ATPase during dietary acidification. As a result, deletion of Epac2 but not Epac1 impaired recovery of intracellular pH after ammonium pulse in A-ICs in split-opened CDs. Conclusion: We showed a novel role of Epac signaling in governing renal adaptation to acid load. While both Epac1 and Epac2 isoforms contribute to controlling NHE-3 expression in the proximal tubule, only Epac2 is necessary to augment H + secretion in the collecting duct thereby contributing to urinary acidification in response to dietary acid load. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.