Generation of endogenous hydrogen sulfide by cystathionine γ-lyase limits renal ischemia/reperfusion injury and dysfunction
Generation of endogenous hydrogen sulfide by cystathionine γ-lyase limits renal ischemia/reperfusion injury and dysfunction
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DOI：
10.1038/labinvest.2008.73
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发表时间：
2008-10-01
影响因子：
5
通讯作者：
Thiemermann, Christoph
中科院分区：
文献类型：
--
作者：
Tripatara, Pinpat;Patel, Nimesh S. A.;Thiemermann, Christoph
内源性硫化氢的产生可能限制或加重了缺血/再灌流引起的组织损伤程度。选用74只雄性Wistar大鼠，观察内源性和外源性硫化氢在肾缺血再灌注损伤中的作用。给予不可逆型半胱硫氨酸-γ-裂解酶(CSE)抑制剂dL-炔丙基甘氨酸可阻止缺血45min再灌流72h后肾功能的恢复。硫化氢供体氢化钠可减轻45min缺血再灌流6h所致的肾、肾小管和肾小球功能障碍和损伤。再灌流30min时肾脏的Western印迹分析显示，硫化钠显著抑制丝裂原活化蛋白激酶(p-38、c-jun氨基末端蛋白激酶1/2和细胞外信号调节蛋白激酶1/2)的磷酸化和核因子-kappaB的激活。再灌流6h，硫化钠显著减轻急性肾小管坏死的组织学评分、caspase-3和Bid的激活、抗细胞凋亡的bc-2表达下降和核因子-kappaB依赖蛋白(诱导型一氧化氮合酶、环氧合酶-2和细胞间黏附分子-1)的表达。这些结果提示：(1)CSE合成内源性硫化氢是保护肾脏免受缺血/再灌注损伤和功能障碍的关键，并有助于缺血/再灌流后肾功能的恢复；(2)硫化氢钠产生的硫化氢可减轻缺血/再灌注损伤和功能障碍，减轻肾脏的形态变化；(3)硫化氢的保护作用既有抗细胞凋亡作用，又有抗炎作用。
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-kappa B. 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-kappa B-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.