Deletion of Epac1 or Epac2 compromises renal Na+ conservation by decreasing activity of the epithelial Na+ channel (ENaC)

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Exchange proteins directly activated by cAMP (Epac1 and Epac2), along with protein kinase A (PKA), are major downstream effectors of the universal intracellular second messenger cAMP, which serves as a nexus of multiple endocrine inputs to regulate renal tubule water and electrolyte transport. We previously demonstrated that deletion of either Epac isoform, namely Epac1 or Epac2, diminishes urinary concentrating ability by reducing fluid reabsorption in the proximal tubule. Here, we employed balance studies in combination with direct electrophysiological assessment of Na+ influx in distal tubule segments from mice with targeted deletion of Epac1 or Epac2 to investigate the role of Epac cascade in tuning urinary Na+ excretion during variations in dietary salt intake. 24 h urinary Na+ levels were comparable in Epac WT and Epac isoform knockouts when animals were subjected to a regular salt intake (0.32% Na+). In contrast, we detected a delayed anti‐natriuretic response during the first 2 days of dietary sodium restriction (<0.01% Na+), which was more pronounced in Epac2 “−/− mice. Consistently, patch clamp analysis in freshly isolated split‐opened collecting ducts found indistinguishable activity (NPo) of the epithelial Na+ channel (ENaC) between Epac WT and Epac2 −/− mice on a regular salt intake: 0.37±0.03 and 0.36±0.05, respectively. Low salt diet greatly increased ENaC activity in Epac WT to 0.75±0.05 as expected, whereas this response was significantly blunted in Epac2 −/− mice (NPo = 0.48 ± 0.06). This was associated with a decrease in both number of active channels per patch and ENaC open probability. In summary, our results support a role of Epac signaling cascade (with a higher contribution of Epac2) in stimulation of ENaC activity by dietary salt restriction. We further propose that reduced ENaC‐mediated Na+ reabsorption at least partially contributes to impaired renal salt conservation in mice with deleted Epac isoforms.Support or Funding InformationNational Institutes of Health (NIH)‐National Institute of Diabetes and Digestive and Kidney Diseases Grants DK119170 (to O.P.), AHA Grant 17GRNT33660488 (to O.P.), ASN Ben J. Lipps Research Fellowship (to V.T.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.