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Am J Physiol Renal Physiol 297: F362-F370, 2009. First published May 27, 2009; doi:10.1152/ajprenal.90609.2008
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Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats

Dae Eun Choi,1 Jin Young Jeong,1 Beom Jin Lim,2 Sarah Chung,1 Yoon Kyung Chang,3 Sang Ju Lee,3 Ki Ryang Na,1 Seok Young Kim,3 Young Tai Shin,1 and Kang Wook Lee1

1Internal Medicine, Chungnam National University Hospital, Daejeon; 2Pathology, Gangnam Severance Hospital, Seoul; and 3Internal 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)






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