COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

Abstract

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

Regulation and function of renal medullary cyclooxygenase-2 during high salt loading

“…In vitro and in vivo results suggested a crucial role of COX-2 in mediating upregulation of renal medullary (pro)renin receptor (PRR) expression and rennin content during ANG II-induced hypertension. (18, 61). Our subsequent study further claimed that the specific COX-2/PGE 2 /EP 4 pathway mediated the upregulation of renal medullary PRR expression by ANGII, leading to activation of intrarenal RAS and enhancement of the hypertensive response (62).…”

(Pro)renin receptor contributes to regulation of renal epithelial sodium channel

“…Recently, Wang et al . [32], demonstrated that PRR is expressed in primary rat IMCD and indicated that Ang II upregulates PRR expression. Similarly, Ang II has been shown to upregulate SGK-1 and ENaC expression [28,33].…”

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

“…In addition, PRR expression levels are regulated by Ang II through CREB (cAMP response element binding protein) in the central nervous system (CNS) during hypertension (W. Li, et al, 2015), and a cyclooxygenase (COX)-2–dependent pathway in the kidney (Wang, et al, 2014). Increased PRR expression may further promote the production of Ang II, ultimately resulting in positive feedback regulation of the receptor itself and the development of hypertension (Wang, et al, 2014; T.…”