Hyperbilirubinemia Induces Pro-Apoptotic Effects and Aggravates Renal Ischemia Reperfusion Injury
Hyperbilirubinemia Induces Pro-Apoptotic Effects and Aggravates Renal Ischemia Reperfusion Injury
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DOI：
10.1159/000496066
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发表时间：
2019-01-01
期刊：
影响因子：
2.5
通讯作者：
Lyu, Lin
中科院分区：
文献类型：
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作者：
Yuan, Li;Liao, Ping-Ping;Lyu, Lin
目的：高胆红素血症与接受心脏手术的患者术后急性肾损伤相关。高浓度胆红素可诱导氧化应激和细胞凋亡。本研究旨在探讨高胆红素血症是否加重肾小管细胞损伤及胆红素对肾缺血再灌注损伤（RIRI）的促凋亡作用。方法：用不同浓度的胆红素作用于人近端肾小管上皮细胞株HK-2细胞24 h。流式细胞术和MTT法检测细胞损伤程度。雄性Sprague-Dawley大鼠腹腔注射胆红素100 mg/kg，每12 h 1次，共3次。在非胆红素注射组中，使用相同体积的溶剂（不含胆红素粉末）作为溶媒。RIRI手术程序是双侧肾蒂夹闭（45分钟），然后再灌注30小时。将大鼠分为4组：阴性对照组（NC），不夹闭; Bil组，胆红素注射36 h后处死; RIRI组，RIRI手术组; Bil + RIRI组，在第一次胆红素注射后6 h应用RIRI，再过30 h处死。结果：胆红素在体外可诱导HK-2细胞凋亡，并使细胞活力明显下降。胆红素可诱导HK-2细胞caspase-3活化和p38磷酸化。在体内，与RIRI相比，Bil + RIRI中的血清肌酐更高（p < 0.01）。HE染色肾小管损伤评分和高碘酸Schiff染色肾小管坏死评分Bil + RIRI组均高于RIRI组（均P < 0.05）。与RIRI相比，Bil + RIRI中Tunel阳性核的数量更高（p < 0.001）。与RIRI相比，Bil + RIRI中活性caspase 3和p38磷酸化水平较高，Bcl 2水平较低。此外，与NC相比，Bil中的凋亡水平更高。结论：高胆红素血症可诱导细胞凋亡，增强RIRI。(C)2019 S. Karger AG，巴塞尔
Aims: Hyperbilirubinemia is associated with postoperative acute kidney injury in patients undergoing cardiac surgeries. A high concentration of bilirubin could induce oxidative stress and cell apoptosis. The aim of this study was to investigate whether hyperbilirubinemia aggravated the renal tubule cells injury and the pro-apoptotic potential of bilirubin on renal ischemia reperfusion injury (RIRI). Methods: The human proximal tubular epithelial cell line HK-2 cells were challenged with a gradient concentration of bilirubin for 24 h. Cell injury was assessed by flow cytometry and MTT assay. Bilirubin was injected intraperitoneally into male Sprague-Dawley rats once every 12 h (100 mg/kg), 3 times in total. The same solvent volume without bilirubin powder was used as vehicle in non-bilirubin injection groups. The RIRI surgical procedure was a bilateral renal pedicles clamping (45 min) followed by 30 h reperfusion. The rats were divided into 4 groups: negative control (NC), similar surgical procedures without clamping; Bil, bilirubin injection for 36 h, then rats were sacrificed; RIRI, RIRI surgical procedures; Bil + RIRI, RIRI applied 6 h later than the first bilirubin injection, rats were sacrificed after another 30 h. Results: In vitro, bilirubin induced cell apoptosis and significantly decreased the cell viability of HK-2 cells. Bilirubin induced the active caspase 3 and phosphorylation of p38 in HK-2 cells. In vivo, serum creatinine was higher in Bil + RIRI compared with RIRI (p < 0.01). The tubular injury scores of hematoxylin and eosin and tubular necrosis scores of periodic acid-Schiff were higher in Bil + RIRI than these in RIRI (All p < 0.05). The number of Tunel-positive nuclei was higher in Bil + RIRI compared to RIRI (p < 0.001). The active caspase 3 and phosphorylation of p38 were higher and the Bcl2 was lower in Bil + RIRI compared to RIRI. Moreover, the apoptosis level was higher in Bil compared to NC. Conclusions: Our results reveal that the hyperbilirubinemia induces pro-apoptotic effects and aggravates RIRI. (C) 2019 S. Karger AG, Basel