Effects of Combination Therapy with Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker on the Injury of Renal Tubulointerstitium in an Unilateral Ureteral Obstruction Rat Model / 대한신장학회잡지

ABSTRACT

BACKGROUND: Unilateral ureteral obstruction(UUO) is an experimental model of tubulointerstitial injury, characterized by progression of interstitial fibrosis and tubular atrophy. In the pathogenic mechanism of renal injury, activation of renin-angiotensin system may play an important role. METHODS: We tested the hypothesis that tubulointerstitial injury begins with infiltration of macrophage, followed by enhanced expression of chemoattractants such as MCP-1 and osteopontin, which are affected by local angiotensin II activity. We examined the beneficial effects of ACEI and AT1RB and combination of these two drugs, with kidney after 5 days of ureter ligation. RESULTS: Monocyte/macrophage infiltration demonstrated by ED-1 staining was markedly increased in UUO group comparing to that of sham operared group, and it was reduced by administeration of ACEI, AT1RB and combination of both, but not statistically significant. MCP-1 mRNA expression increased significantly after 5 days of UUO. ACE inhibitor, enalapril treatment had suppressed significantly the MCP-1 mRNA expression level, but AT1RB, candesartan had not significance. Combination of both made no more reduction of MCP-1 mRNA level compared to ACEI alone. The other macrophage chemoattractant protein, osteopontin expression was examined by immunohistochemistry, and evaluated with image analysis. Marked up-regulated osteopontin expression was observed on the brushborder of proximal tubules after 5 days UUO. There was a great reduction of osteopontin expression in a enalapril treated group and more significant reduction was noted in the group, treated with combination of both. candesartan did not reduce osteopontin expression. CONCLUSION: This study suggest that activation of renin-angiotensin system has a major role in the pathogenesis of tubulointerstitial renal injury in UUO through expression of chemoattractants and infiltration of inflammatory cells. Blocking of this process may inhibit renal injury process and ACEI halts these process but AT1RB does not. Combination use of both drugs did not show more additive effect compare to ACEI use alone in the phase of early inflammatory process of renal injury.