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.