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Exchange Protein Directly Activated by cAMP Isoform 2 (Epac2) but Not Isoform 1 (Epac1) Is Critical for Renal Acid‐Base Handling

Cyclic adenosine monophosphate (cAMP) is a critical second messenger of numerous systemic and local signals affecting water‐electrolyte transport and pH regulation by the renal tubule. Exchange proteins directly activated by cAMP (Epacs) are guanine nucleotide exchange factors commonly operating independently from the classical cAMP‐protein kinase A (PKA) signaling. We previously demonstrated that both Epac isoforms, namely Epac1 and Epac2 are functionally expressed in the proximal tubule and the collecting duct. Epac1 ‐/‐ and Epac2 ‐/‐ mice exhibit urinary concentrating defect and salt wasting in response to hypovolemia. Since the proximal tubule and the collecting duct are central for urinary acid/base excretion, we examined the role of Epac1 and Epac2 in maintaining systemic pH balance. EpacWT, Epac1‐/‐, and Epac2 ‐/‐ mice had comparable arterial pH of 7.33±0.02, 7.33±0.04, and 7.30±0.02 respectively at the baseline. However, urinary pH was significantly lower only in Epac2 ‐/‐ (5.96±0.06), but not Epac1 ‐/‐ (6.61±0.15) when compared to EpacWT (6.90±0.38). Acid loading with NH4Cl supplementation in water for 3 days mildly reduced arterial pH in EpacWT and Epac1‐/‐ to 7.27±0.01 and 7.24±0.03 respectively, but induced significantly greater acidosis (7.12±0.03) in Epac2 ‐/‐ mice. This was also associated with significantly lower blood HCO3‐ levels in Epac2 ‐/‐ compared to Epac1‐/‐ and EpacWT: 18±1 mM/l, 23±2 mM/l, and 23±1 mM/l, respectively. Furthermore, NH4Cl supplementation led to marked reduction in urinary pH levels of EpacWT and Epac1‐/‐, but failed to significantly decrease already low urinary pH in Epac2 ‐/‐ (5.86±0.03). While NHE‐3 levels in the proximal tubule were significantly reduced in Epac1‐/‐mice (~50%), this was more pronounced in Epac2‐/‐ mice (~90%). Furthermore, pHi analysis in freshly isolated split‐opened collecting ducts revealed altered recovery after acidification in intercalated cells of Epac2‐/‐ mice. Overall, we report that Epac2 plays a critical role in renal adaptation to acidification. Epac2 deficiency compromises urinary acid excretion by reducing NHE‐3 expression in the proximal tubule and distorting titratable acid excretion by the collecting duct intercalated cells leading to severe acidosis. In contrast, Epac1 does not play a major role in renal acid/base handling. The observed reduction in NHE‐3 levels in Epac1‐/‐ are effectively compensated by the acid excretion in the collecting duct and thus does not lead to prominent alteration in blood pH. We speculate that pharmacology‐based manipulation with Epac2, but not Epac1 might be of relevance in managing acid‐base disorders in the clinical setting.