A4312 Role of (Pro) Renin Receptor in Protein-Overload Nephropathy in Rats

Abstract

Objectives: Proteinuria is not only a common feature of chronic kidney diseases (CKD), but also an independent risk factor for accelerated CKD progression to end-stage renal failure. Therefore, mitigating proteinuria may be an effective strategy for treating CKD. However, currently the molecular mechanism underlying proteinuria-induced CKD remains largely elusive. To this end, the present study was designed to understand the role of the (pro) renin receptor (PRR) in albumin overload (OA)-induced nephropathy, which involves the activation of the local renin-angiotensin system (RAS). Methods: Unilateral nephrectomy was performed on Wistar rats, which were then treated for 7 weeks with vehicle, bovine serum albumin (BSA) (5 g/kg/d via a single i.p. injection) or BSA plus a PRR decoy inhibitor PRO20 (500 μg/kg/d via 3 s.c. injections). Results: OA rats exhibited severe proteinuria, tubular necrosis, interstitial fibrosis, oxidative stress, inflammation, and urinary N-acetyl-beta-D-glucosaminidase activity and β2 microglobulin secretion. Simultaneous administration of PRO20 significantly attenuated all symptoms, and improved indices of the intrarenal RAS, including renal and urinary renin, angiotensinogen and angiotensin II levels. OA rats also showed increased expression of full-length PRR and soluble PRR (sPRR) in the renal cortex, and the level of urinary sPRR was increased by ∼5 fold. Conclusion: Taken together, our data showed that PRR antagonism demonstrated renoprotective effects against OA-induced nephropathy by inhibiting the intrarenal RAS, thereby providing scientific evidence supporting clinical intervention of the local RAS for treating hypertensive disorders and CKD.