Hypertension is a common chronic disease with a significant impact on public health, yet its basic pathogenesis is not fully understood, and new therapeutic targets are needed. A beneficial role for prostanoids in hypertension was suggested because non-steroidal anti-inflammatory drugs (NSAIDs), which block the production of all prostanoids, can cause sodium retention and exacerbate hypertension. Among prostanoids, PGE2 and its EP4 receptor (EP4R) have been implicated in blood pressure control, but these mechanisms are unknown. Our previous work showed that conditional deletion of EP4R from all tissues in adult mice dramatically exacerbated Ang II-dependent hypertension. However, the elimination of EP4R from vascular smooth muscle cells, endothelial cells, and macrophages had no impact on hypertension development. By contrast, specific removal of EP4R from whole renal epithelia recapitulated the phenotype of exacerbated hypertension, indicating that EP4R attenuates hypertension by direct actions in the renal epithelium. Recent single-cell sequencing studies demonstrated that EP4R expression in renal epithelia is enriched in the collecting duct (CD). CDs have pivotal roles in final urinary sodium excretion through the actions of the epithelial sodium channel (ENaC). Our preliminary studies showed that mice with EP4R deletion in renal epithelia throughout the nephron had increased responsiveness to ENaC inhibitor, and PGE2 inhibits the ENaC activity in isolated CDs. Thus, we hypothesize that EP4R resists the development of hypertension through actions in the CD to reduce sodium reabsorption via ENaC. The project’s objective is to identify mechanisms underlying the anti-hypertension effects of EP4R and to exploit them for new treatments of human hypertension. Our Aims are: 1) Identify cell specificity for EP4R actions in kidney epithelia to resist hypertension. We will generate mice with EP4R deleted from entire CDs, principal cells, or intercalated cells, respectively, to assess the consequences of these genetic alterations on blood pressure, sodium homeostasis, and ENaC function in hypertension; and 2) Determine the mechanisms of ENaC regulation by EP4R. We will perform patch-clamp electrophysiology in isolated CDs to characterize EP4R downstream signaling pathways that mediate its powerful effects on attenuating the development of hypertension. Successful completion of the proposed research is expected to identify the mechanisms underlying the antihypertensive actions of EP4R. The long-term goal is to identify novel therapeutic targets for essential hypertension.