Role of (Pro)Renin Receptor in Cyclosporin A-Induced Nephropathy

Am J Physiol Renal Physiol. 2022 Jan 24. doi: 10.1152/ajprenal.00332.2021. Online ahead of print.ABSTRACTCalcineurin inhibitors (CNIs) such as cyclosporin A (CsA) have been widely used to improve graft survival following solid-organ transplantation. However, the clinical use of CsA is often limited by its nephrotoxicity. The present study tested the hypothesis that activation of (pro)renin receptor (PRR) contributes to CsA-induced nephropathy by activating the renin-angiotensin system (RAS). Renal injury in male Sprague-Dawley rats was induced by a low-salt diet combined with CsA as evidenced by elevated plasma creatinine and BUN levels, decreased creatinine clearance and induced renal inflammation, apoptosis as well as interstitial fibrosis, elevated urinary N-acetyl-β-D-glucosaminidase activity and urinary kidney injury molecular 1 content. Each index of renal injury was attenuated following a 2-wk treatment with a PRR decoy inhibitor PRO20. While CsA rats with kidney injury displayed increased renal sPRR abundance, plasma sPRR, renin activity, Ang II, and heightened urinary total prorenin/renin content; RAS activation was attenuated by PRO20. Exposure of cultured human renal proximal tubular HK-2 cells to CsA induced expression of fibronectin and sPRR production, but the fibrotic response was attenuated by PRO20 and siRNA-mediated PRR knockdown. These findings support the hypothesis that activation of PRR contributes to CsA-induced nephropathy by activating the RAS in rat...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Source Type: research