Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats

1 Internal Medicine, Chungnam National University Hospital, Daejeon; 2 Pathology, Gangnam Severance Hospital, Seoul; and 3 Internal Medicine, Daejeon Saint Mary Hospital, Daejeon, Republic of Korea Submitted 14 October 2008 ; accepted in final form 26 May 2009 Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1 , male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2 , we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio. apoptosis; ERK Address for reprint requests and other correspondence: K. W. Lee, Internal Medicine, Chungnam National Univ. Hospital, 640 Daesadong, Chunggu Daejeon, Republic of Korea (e-mail: kwlee{at}cnu.ac.kr )