MP29-09 RENO-PROTECTIVE EFFECT OF LOCAL SILDENAFIL ADMINISTRATION IN CANINE MODEL OF RENAL ISCHEMIA REPERFUSION INJURY

Abstract

INTRODUCTION AND OBJECTIVES: The reno-protective effect of systemic Sildenafil administration in renal ischemia reperfusion injury (IR) animal models has been proved. Nevertheless, the local effect of Sildenafil on IRhas not been established yet. Therefore, we designed a new canine model of IR injury to investigate the effect of local Sildenafil administration during renal ischemia. METHODS: One hundred and twenty male mongrel dogs were classified into 5 groups (each consists of 24 dogs): sham (underwent right nephrectomy without ischemia), oral control (underwent right nephrectomy and left ischemia for 60 min), oral Sildenafil (OS) group (as control with oral Sildenafil 1mg/kg 60 min before ischemia), local control (local perfusion of ischemic left kidney with saline and heparinfor 5min) and local Sildenafil (LS) group (the same as local control with addition of Sildenafil 0.5 mg/kg to the perfusion solution). Serum creatinine (SCr), blood urea nitrogen (BUN) and radioisotope renography were measured at 1, 3, 7 and 14 days. Histopathological examination of the inner cortex and outer medulla was performed by non-informed pathologist. In kidney tissues, mRNA ofantioxidants glutathione reductase (GSH), sodium dismutase (SOD), and endothelial nitric oxide synthase (eNOS) were measured. Oxidative stress markers e.g. malondialdehyde (MDA), and angiogenesis markers e.g. vascular endothelial growth factor (VEGF) were assessed. Similarly, markers of inflammation e.g. Tumor necrosis factor-a (TNF-a), interleukin1s (IL1s), and intracellular adhesion molecule (ICAM-1) were assessed. The expression of cleaved caspase-3 was assessed by immunohistochemical staining. RESULTS: Serum creatinine, BUN and GFR improved significantly in Sildenafil-treated groups in comparison to their control groups with LS had better improvement than OS (p<0.05) (Fig. 1). LS showed significant attenuation of cortical and outer medullary damage scores and less neutrophil infiltration than other groups. Sildenafil-treated groups showed higher expression of antioxidant markers than control groups while LS has higher antioxidant markers than OS (p<0.05). Sildenafil-treated groups showed lower expression of oxidative stress, angiogenesis and inflammatory markers than control groups (p<0.05). LS had lower expression of these markers as well as apoptotic markers than OS (p<0.05). CONCLUSIONS: Sildenafil has a reno-protective effect via its anti-apoptotic, anti-inflammatory, and antioxidant effects. Local administration of Sildenafil seems to be more effective than systemic administration. These results may provide a base for its application in the process of renal transplantation in human during renal perfusion.