Renal Epac signaling is necessary for setting salt-sensitivity of blood pressure

Background: Hypertension is the major global public health concern, affecting over 25% of population in the U.S. and Worldwide. Kidneys play a central role in regulation of blood pressure (BP) by controlling urinary Na + excretion. Exchange proteins directly activated by cAMP (Epac1 and Epac2) are highly expressed in the renal tubule, particularly in the proximal tubule and the collecting duct system. We previously reported that global deletion of Epac1 and/or Epac2 increases urinary volume and impairs renal Na + conservation. However, the physiological relevance of renal Epac isoform expression for the overall kidney function and blood pressure control remains unknown. Methods: Here, we utilized transgenic mouse models lacking Epac1 and Epac2 globally and selectively in the kidney using cre-loxP strategy with renal tubule specific Pax8 cre. BP was registered at the same timeframe (10-11AM) with an improved tail cuff plethysmography. To establish salt-sensitivity, animals were fed with either regular (0.32% Na + ) or sodium-deficient (< 0.01% Na + ) diet for 7 days. Renal function, a.k.a. glomerular filtration rate (GFR) was assessed with fluorescent method following retroorbital bolus injection of (FITC)-sinistrin. Results: Global deletion of both Epac isoforms did not lead to measurable differences in both systolic and diastolic BP from the WT when animals were maintained on regular Na + regimen. However, this was achieved at the expense of a significantly lower GFR in Epac1&2 -/- mice by approximately 30% indicative of impaired renal Na + handling. Dietary Na + deficiency did not alter BP in EpacWT mice, whereas it led to a significant reduction in the mean arterial pressure by 26% in Epac1&2 -/- mice thereby unmasking the defective Na + reabsorption in the knockouts. Moreover, the WT but not Epac1&2 -/- mice were able to reduce GFR in response to Na + deficient diet. Importantly, kidney specific deletion of either Epac1 or Epac2 recapitulated the hypotensive response to dietary Na + restriction seen in the knockout with global Epac deletion. This was at least partially attributed to the reduction in the expression levels and activity of NHE-3 and ENaC, the major sodium transporters in the proximal tubule and the collecting duct, respectively. The activity of the transporters was assessed with patch clamp electrophysiology and fluorescent pH i microscopy in ex vivo preparations upon genetic ablation of individual or both Epac isoforms. Conclusions: In summary, our results demonstrate that renal Epac signaling is indispensable to control Na + reabsorption and, by extension, blood pressure during variations in dietary Na + intake. This research was supported by NIDDK DK117865, DK136462, AHA 20EIA35260097 (to O. Pochynyuk), AHA 24POST1191738 (to A. Atamanchuk) and AHA 24SCEFIA1259812 (to K. Pyrshev). This abstract was presented at the American Physiology Summit 2025 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.