Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy
Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy
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DOI：
10.1097/01.tp.0000287334.38933.e3
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发表时间：
2007-11-15
期刊：
影响因子：
6.2
通讯作者：
Lai, Ming-Kuen
中科院分区：
文献类型：
--
作者：
Chien, Chiang-Ting;Shyue, Song-Kuen;Lai, Ming-Kuen
背景资料。细胞凋亡和自噬可能通过线粒体损伤促进肾缺血/再灌流损伤的细胞内稳态。缺血/再灌流通过分离的Bclxl表达诱导近端和远端小管的不同敏感性。我们假设在近端和远端肾小管中增加bc l-xl可能会潜在地减轻缺血/再灌流引起的肾功能障碍。我们通过肾内腺病毒BCL-XL基因转移增强了大鼠肾脏中BclXL蛋白的表达，并评价了BclXL增强对大鼠肾脏缺血/再灌流诱导的肾脏氧化应激、细胞凋亡和自噬的潜在影响。肾动脉注射Adv-bc1-xl可增强大鼠肾组织中bclxl蛋白的最大表达。Bclxl的主要增强部位在近、远端肾小管，而在肾小球内未见。缺血再灌注增加线粒体细胞色素C释放、肾组织O-2(-)水平和3-硝基和4-羟色胺积聚，促进肾小管细胞凋亡和自噬，包括微管相关蛋白1轻链3(LC-3)和Beclin-1表达增加，Bax/Bclxl比值增加，caspase3表达和多聚(ADP-核糖)聚合酶片段增加，进而导致近端和远端肾小管的凋亡/自噬。而ADV-BCL-XL可显著降低缺血再灌注损伤大鼠肾小管上皮细胞线粒体细胞色素C释放、O-2(-)生成、3-硝基酪氨酸和4-羟基非肾素积聚、Beclin-1表达、Bax/Bax-YL比值和近、远端肾小管细胞凋亡/自噬，从而改善肾功能障碍。进一步研究表明，在改善缺血/再灌流诱导的近、远端肾小管细胞凋亡和肾功能不全方面，BclxL增强比Bcl2增强更有效。我们的结果表明，ADV-bclxl基因转移通过下调肾小管细胞凋亡和自噬而显著改善缺血/再灌注所致的肾功能障碍。
Background. Apoptosis and autophagy may contribute to cell homeostasis in the kidney subjected to ischemia/reperfusion injury via mitochondrial injury. Ischemia/reperfusion induces differential sensitivity between proximal and distal tubules via a dissociated Bcl-xL expression. We hypothesized Bcl-xL augmentation in the proximal and distal tubules may potentially reduce ischemia/reperfusion induced renal dysfunction.Methods. We augmented Bcl-xL protein expression in the kidney with intrarenal adenoviral bcl-xL gene transfer and evaluated the potential effect of Bcl-xL augmentation on ischemia/reperfusion induced renal oxidative stress, apoptosis, and autophagy in the rat.Results. Intrarenal arterial Adv-bcl-xL administration augmented maximal Bcl-xL protein expression of rat kidney after 7 days of transfection. The primary location of Bcl-xL augmentation was found in proximal and distal tubules, but not in glomeruli. Ischemia/reperfusion increased mitochondrial cytochrome C release, renal O-2(-) level and renal 3-nitrosine and 4-hydroxyneonal accumulation, potentiated tubular apoptosis and autophagy, including increase in microtubule-associated protein 1 light chain 3 (LC-3) and Beclin-1 expression, Bax/Bcl-xL ratio, caspase 3 expression and poly-(ADP-ribose)-polymerase fragments, and subsequent proximal and distal tubular apoptosis/autophagy. However, Adv-bcl-xL administration significantly reduced ischemia/reperfusion enhanced mitochondrial cytochrome C release, O-2(-) production, 3-nitrotyrosine and 4-hydroxynonenal accumulation, Beclin-1 expression, Bax/Bcl-YL ratio, and proximal and distal tubular apoptosis/autophagy, consequently improving renal dysfunction. Further study showed that Bcl-xL augmentation was more efficiently than Bcl-2 augmentation in amelioration of ischemia/reperfusion induced proximal and distal tubular apoptosis and renal dysfunction.Conclusions. Our results suggest that Adv-bcl-xL gene transfer significantly improves ischemia/reperfusion-induced renal dysfunction via the downregulation of renal tubular apoptosis and autophagy.