Effects of a cGMP-specific phosphodiesterase inhibitor on expression of endothelial nitric oxide synthase and vascular endothelial growth factor in rats with cyclosporine-induced nephrotoxicity.

ABSTRACT

BACKGROUND: The mechanism of cyclosporine (CsA)-induced nephrotoxicity has been suggested to be vasoconstriction due to reduced nitric oxide (NO), providing tissue fibrosis by elevation of transforming growth factor beta and vascular endothelial growth factor (VEGF). In this study using a rat model of CsA-induced nephrotoxicity, we administered a phosphodiesterase-5 inhibitor to ameliorate the renal injury and alter the expression of endothelial No synthase (eNOS) and VEGF. METHODS: A right nephrectomy was performed in Sprague-Dawley rats (n = 30; 200-250 g, all male). The Ischemia group (n = 6) underwent ligation of the left renal artery for 45 minutes (IR) before observation for 28 days. After IR, the udenafil group (n = 6) was treated with 10 mg/kg drug orally, the CsA group (n = 6) received 15 mg/kg CsA injected subcutaneously and the CsA plus udenafil group (n = 6) received 15 mg/kg CsA injected subcutaneously together with the oral administration of 10 mg/kg udenafil. RESULTS: Administration of udenafil significantly decreased serum creatinine either alone (0.21 ± 0.04 mg/dL) or in combination with CsA (1.86 ± 0.35 mg/dL) versus the ischemia (0.85 ± 0.22 mg/dL) and the CsA alone (3. 10 ± 0.77 mg/dL) group. (P = .002; P = .002). Comparing the Hematoxylin-eosin staining of the ischemia (0.41 ± 0.09) and CsA (0.44 ± 0.08) groups showed a significantly decreased loss of nuclei in proximal tubules after the administration of udenafil (0.27 ± 0.05 [P = .004] and 0.26 ± 0.02 [P = .002] respectively). Immunohistochemical staining showed strong eNOS staining in the udenafil and CsA plus udenafil groups. Western blots for eNOS showed decreased expression in the CsA group and increased expression in the udenafil group. Western blots for VEGF revealed reduced expression only in the CsA plus udenafil group. eNOS mRNA was decreased in the CsA (0.017 ± 0.010) compared with the ischemia group (0.048 ± 0.015; P = .000). VEGF mRNA which was decreased in the CsA group (2.026 ± 1.109), showed greater tendency after administration of udenafil (0.440 ± 0.449) (P = .003). CONCLUSION: The phosphodiesterase inhibitor ameliorated renal injury in a rat model of CsA-induced nephrotoxicity, possibly related to increased eNOS and reduced VEGF expression.