Abstract
Background: Iodinated contrast media (CM) has been broadly used for diagnostic procedures; CM-induced nephropathy (CIN) affects morbidity and mortality of patients. Although CIN is known to be mediated by several factors, including the renin-angiotensin system (RAS), little is known about the evidence obtained from experimental models. Thus, we developed a murine CIN model to evaluate the mechanism. Methods: We performed 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol, 500 μ l/25 g mice) intravenously into the mice 4 weeks after NTX. We administered an angiotensin converting enzyme inhibitor (ACEI, imidapril, 1 mg/kg/day, n=6), an angiotensin II receptor blocker (ARB, TA606, 1 mg/kg/day, n=4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, 0.25 mg/kg, n=5) into the mice daily. Results: Serum creatinine levels on day 28 were significantly elevated in the NTX group (0.26±0.01 mg/dl) compared to those in the non-NTX group (0.13±0.01 mg/dl). A day after CM injection, creatinine levels were significantly elevated in the non-treated group (0.41±0.01 mg/dl). While ACEI treatment significantly suppressed the increase in creatinine levels (0.34±0.04 mg/dl, p<0.05 vs. CIN group), ARB treatment did not suppress (0.47±0.06 mg/dl). A bradykinin antagoninst Hoe-140 negated (0.43±0.07 mg/dl, p<0.05 vs. CIN+ACEI) ACEI’s ability to suppress renal damage. We examined renal AT1R, COX-2, MCP-1 and MMP-9 mRNA levels using quantitative RT-PCR. AT1R mRNA levels were enhanced in the NTX and CIN groups compared to those in the native group. COX-2, MCP-1 and MMP-9 mRNA levels were enhanced in the CIN+ACEI group compared to the native and CIN groups. ACEI+Hoe-140 treatment suppressed the mRNA expression. Both treatments did not reduce their blood pressure compared to those of the vehicle treatment, statistically. Conclusion: ACEI treatment is useful for the prevention of CM-induced nephropathycompared to that of ARB treatment in the murine model of CIN because bradykinin pathway is critical in regulating CIN development.
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