Loss of OXGR1 function uncouples intrarenal RAS activation from pendrin and αENaC regulation and blunts angiotensin II-induced hypertension.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) is a key mechanism driving sodium retention and hypertension. In the distal nephron, locally generated angiotensin II (Ang II) promotes Na+ reabsorption through coordinated regulation of the epithelial Na+ channel (ENaC) in principal cells and electroneutral NaCl transport mediated by pendrin and the Na+-dependent Cl-/HCO3- exchanger (NDCBE) in intercalated cells. Emerging evidence identifies α-ketoglutarate as an intrarenal paracrine signal acting through oxoglutarate receptor 1 (OXGR1), which is highly expressed in collecting duct intercalated cells. We hypothesized that OXGR1 is required to couple intrarenal RAS activation with collecting duct Na+ transport and blood pressure regulation during Ang II-dependent hypertension. METHODS: mice were subjected to chronic Ang II infusion (400 ng·min-1·kg-1, 14 days) using two approaches: pharmacological OXGR1 blockade with montelukast (3.5 μg ·min-1·kg-1) and global OXGR1 genetic deletion (OXGR1-/-). Blood pressure, Na+ balance, and the renal abundance of pendrin, NDCBE and αENaC were assessed. Intrarenal RAS activity was evaluated by measuring Ang I (renin activity), Ang II, ACE activity and (pro)renin receptor (PRR). RESULTS: Ang II infusion increased blood pressure, promoted antinatriuresis, and elevated intrarenal Ang II, ACE activity, PRR, pendrin, and αENaC protein abundance. In contrast, both montelukast-treated wild type and OXGR1-/- mice infused with Ang II displayed attenuated hypertensive responses, reduced Na+ retention, and failed to increase intrarenal Ang II, pendrin, or αENaC abundance. CONCLUSION: These findings identify OXGR1 as a critical regulator linking intrarenal RAS activation to distal nephron Na+ transport and suggest that OXGR1-dependent signaling contributes to sodium retention and the development of Ang II-induced hypertension.