(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting the intrarenal renin-angiotensin system

摘要

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg-1·day-1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.