Crosstalk between (Pro)renin receptor and COX-2 in the renal medulla during angiotensin II-induced hypertension

- AngII infusion induces parallel increases in renal medullary expression of PRR and COX-2.
- PRR activation increases PGE2 release and COX-2 expression via ERK1/2.
- COX-2-derived PGE2via EP4 stimulates PRR expression and renin activity.
- The interaction of PRR and COX-2 is a key to AngII-induced renin response in the distal nephron.

Angiotensin II (AngII) is an octapeptide hormone that plays a central role in regulation of sodium balance, plasma volume, and blood pressure. Its role in the pathogenesis of hypertension is highlighted by the wide use of inhibitors of the renin-angiotensin system (RAS) as the first-line antihypertensive therapy. However, despite intensive investigation, the mechanism of AngII-induced hypertension is still incompletely understood. Although diverse pathways are likely involved, increasing evidence suggests that the activation of intrarenal RAS may represent a dominant mechanism of AngII-induced hypertension. (Pro)renin receptor (PRR), a potential regulator of intrarenal RAS, is expressed in the intercalated cells of the collecting duct (CD) and induced by AngII, in parallel with increased renin in the principal cells of the CD. Activation of PRR elevated PGE2 release and COX-2 expression in renal inner medullary cells whereas COX-2-derived PGE2via the EP4 receptor mediates the upregulation of PRR during AngII infusion, thus forming a vicious cycle. The mutually stimulatory relationship between PRR and COX-2 in the distal nephron may play an important role in mediating AngII-induced hypertension.