The Synergistic Effect of Mizoribine and a Direct Renin Inhibitor, Aliskiren, on Unilateral Ureteral Obstruction Induced Renal Fibrosis in Rats

Abstract

Renal fibrosis, the major histopathological change in various renal disorders, is closely related to renal dysfunction. Unilateral ureteral obstruction is a well established model of experimental renal disease that results in tubulointerstitial fibrosis. Previous studies showed that aliskiren and mizoribine ameliorated unilateral ureteral obstruction induced renal fibrosis. However, to our knowledge the protective effect of combination therapy with aliskiren and mizoribine against renal fibrosis is unknown. We investigated the synergistic effects of aliskiren and mizoribine combination therapy on unilateral ureteral obstruction induced fibrosis in rats. Male Sprague Dawley® rats underwent unilateral ureteral obstruction followed by aliskiren and/or mizoribine treatment. Kidney samples were fixed for histopathology and immunohistochemistry of myofibroblasts (α-SMA) and macrophages (ED-1). Real-time quantitative reverse transcription-polymerase chain reaction was performed to measure α-SMA, TGF-β1, osteopontin, MCP-1 and renin expression. After unilateral ureteral obstruction the tubular dilatation, interstitial volume and α-SMA expression scores were significantly decreased by combination therapy compared with monotherapy with aliskiren or mizoribine. Combination therapy caused a significant decrease in the number of ED-1 positive cells and in TGF-β1 gene expression compared with monotherapy with either drug (each p <0.05). Combination therapy also decreased OPN and MCP-1 gene expression (p <0.05). Aliskiren and mizoribine combination therapy provides increased renal protection against renal fibrosis and unilateral ureteral obstruction induced inflammation.