Synergistic Contribution of Epac1‐/‐ and Epac2‐/‐ for Urinary Concentrating Ability.

R2738 --> 855.3 --> Epac is a relatively new direct downstream effector of cAMP. Two known Epac isoforms, Epac1 and Epac2 are abundantly expressed in the renal epithelial cells of the proximal tubule and the collecting duct. We recently demonstrated that Epac1‐/‐ and Epac2‐/‐ mice develop polyuria largely due to decreased NHE‐3 expression in the proximal tubule. In contrast, AQP2‐dependent water reabsorption in the collecting duct was unaffected. In this study, we utilized double Epac knockout mice to determine whether both isoforms contribute complementarily to the urinary production and concentrating ability. We found that Epac1&2‐/‐ produced significantly higher 24h urinary volume and lower osmolarities compared to the values in single Epac knockouts. These differences were further exacerbated in response to water deprivation test suggesting a defect in the collecting duct. Consistently, Epac1&2 blockade with ESI‐09 inhibited AQP2 translocation to the apical plasma membrane in CD cells in response to AVP. At the same time, inhibition of a single Epac isoform fails to do so. Overall, our results demonstrate that concomitant Epac1‐/‐ and Epac2‐/‐deletion compromises reabsorption in both PT and CD, thus leading to a much greater in urine volume and decrease urinary concentrating ability than the single isoform Epac knockout. [ABSTRACT FROM AUTHOR]