Tripatara Pinpat, Patel Nimesh S A, Collino Massimo, Gallicchio Margherita, Kieswich Julius, Castiglia Sara, Benetti Elisa, Stewart Keith N, Brown Paul A J, Yaqoob Mohammed M, Fantozzi Roberto, Thiemermann Christoph
Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Lab Invest. 2008 Oct;88(10):1038-48. doi: 10.1038/labinvest.2008.73. Epub 2008 Aug 4.
The generation of endogenous hydrogen sulfide may either limit or contribute to the degree of tissue injury caused by ischemia/reperfusion. A total of 74 male Wistar rats were used to investigate the effects of endogenous and exogenous hydrogen sulfide in renal ischemia/reperfusion. Administration of the irreversible cystathionine gamma-lyase (CSE) inhibitor, dL-propargylglycine, prevented the recovery of renal function after 45 min ischemia and 72 h reperfusion. The hydrogen sulfide donor sodium hydrosulfide attenuated the (renal, tubular, and glomerular) dysfunction and injury caused by 45 min ischemia and 6 h reperfusion. Western blot analysis of kidneys taken at 30 min reperfusion showed that sodium hydrosulfide significantly attenuated phosphorylation of mitogen-activated protein kinases (p-38, c-JUN N-terminal protein kinase 1/2, and extracellular signal-regulated kinase 1/2) and activation of nuclear factor-kappaB. At 6 h reperfusion, sodium hydrosulfide significantly attenuated the histological score for acute tubular necrosis, the activation of caspase-3 and Bid, the decline in the expression of anti-apoptotic Bcl-2, and the expression of nuclear factor-kappaB-dependent proteins (inducible nitric oxide synthase, cyclo-oxygenase-2, and intercellular adhesion molecule-1). These findings suggest that (1) the synthesis of endogenous hydrogen sulfide by CSE is essential to protect the kidney against ischemia/reperfusion injury and dysfunction and aids in the recovery of renal function following ischemia/reperfusion, (2) hydrogen sulfide generated by sodium hydrosulfide reduces ischemia/reperfusion injury and dysfunction, and morphological changes of the kidney, and (3) the observed protective effects of hydrogen sulfide are due to both anti-apoptotic and anti-inflammatory effects.
内源性硫化氢的产生可能会限制或加重缺血/再灌注引起的组织损伤程度。总共74只雄性Wistar大鼠被用于研究内源性和外源性硫化氢在肾脏缺血/再灌注中的作用。给予不可逆的胱硫醚γ-裂解酶（CSE）抑制剂dL-炔丙基甘氨酸，可阻止45分钟缺血和72小时再灌注后肾功能的恢复。硫化氢供体硫氢化钠可减轻45分钟缺血和6小时再灌注引起的（肾脏、肾小管和肾小球）功能障碍和损伤。对再灌注30分钟时获取的肾脏进行蛋白质免疫印迹分析显示，硫氢化钠可显著减轻丝裂原活化蛋白激酶（p-38、c-JUN N端蛋白激酶1/2和细胞外信号调节激酶1/2）的磷酸化以及核因子-κB的激活。在再灌注6小时时，硫氢化钠可显著减轻急性肾小管坏死的组织学评分、caspase-3和Bid的激活、抗凋亡蛋白Bcl-2表达的下降以及核因子-κB依赖性蛋白（诱导型一氧化氮合酶、环氧化酶-2和细胞间黏附分子-1）的表达。这些发现表明：（1）CSE合成内源性硫化氢对于保护肾脏免受缺血/再灌注损伤和功能障碍至关重要，并有助于缺血/再灌注后肾功能的恢复；（2）硫氢化钠产生的硫化氢可减轻缺血/再灌注损伤、功能障碍以及肾脏的形态学改变；（3）观察到的硫化氢的保护作用是由于其抗凋亡和抗炎作用。
