Abstract
Calcineurin inhibitors 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 the (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 blood urea nitrogen levels, decreased creatinine clearance and induced renal inflammation, apoptosis and interstitial fibrosis, and elevated urinary N-acetyl-β-d-glucosaminidase activity and urinary kidney injury molecule-1 content. Each index of renal injury was attenuated following 2 wk of treatment with the PRR decoy inhibitor PRO20. Although CsA-treated rats with kidney injury displayed increased renal soluble (s)PRR abundance, plasma sPRR, renin activity, angiotensin 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 rats. Of importance, we provide strong proof of concept that targeting PRR offers a novel therapeutic strategy to limit nephrotoxic effects of immunosuppressant drugs.NEW & NOTEWORTHY The present study reports, for the first time, that activation of the (pro)renin receptor drives the renin-angiotensin system to induce renal injury during cyclosporin A administration. More importantly, our study has identified that antagonism with PRO20 offers a novel intervention in the management of side effects of cyclosporin A.