Submitted on October 14, 2008
Revised on May 26, 2009
Accepted on May 26, 2009
Pretreatment of Sildenafil Attenuates Ischemia-Reperfusion(IR) Renal Injury in the Rats
Dae Eun Choi1, Jin Young Jeong1, Beom Jin Lim2, Sarah Chung1, Yoon Kyung Chang3, Sang Ju Lee3, Ki Ryang Na1, Seok Young Kim3, Young Tai Shin1, and Kang Wook Lee1*
1 Chungnam National University Hospital
2 Gangnam Severance Hospital
3 Daejeon Saint Mary's Hospital
* To whom correspondence should be addressed. E-mail: kwlee{at}cnu.ac.kr.
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 SpragueDawley 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 iNOS and 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 TUNEL-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 anti apoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
