GSK-3β在造影剂致肾小管上皮细胞损伤中的作用及机制研究

项目名称： GSK-3β在造影剂致肾小管上皮细胞损伤中的作用及机制研究

项目编号： No.81500508

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 鲍慧

作者单位： 同济大学

项目金额： 18万元

中文摘要： 造影剂肾病是医源性急性肾损伤(AKI)的常见诱因。然而，造影剂诱导AKI的机理不清。我们前期研究发现：1)糖原合成酶激酶-3β（GSK-3β）是肾小管上皮细胞增殖和凋亡的关键调控分子；2)GSK-3β过度活化使线粒体内Cyclophilin F磷酸化，引起线粒体通透性转变孔道开放异常，致细胞凋亡；3)GSK-3β的抑制促增殖蛋白表达导致增殖水平下降；4) 静注造影剂患者血液GSK-3β活化水平增高，同时伴有尿KIM-1和NAG酶的相一致地升高; 5)锂盐通过抑制GSK-3β活性对造影剂致肾小管上皮损伤有保护作用。故认为GSK-3β过度活化是造影剂肾病的关键机制。为此，拟以GSK-3β对肾小管上皮细胞凋亡和损伤后期的增殖作用为切入点, 系统探讨GSK-3β的致病作用及其关键调控通路，预期结果为探索GSK-3β抑制剂（碳酸锂）及干预其相关重要通路的联合治疗造影剂肾损伤新方案提供实验证据。

中文关键词： 急性肾损伤；糖原合成酶激酶3B；；凋亡；细胞增殖；肾脏修复

英文摘要： Contrast-induced nephropathy (CIN) is a well-known cause of hospital-acquired renal failure. Mechanisms of contrast-induced acute kidney injury(CI-AKI) remain obscure. Our previous work has suggested as follows: 1) Glycogen synthase kinase (GSK) 3β has emerged as the integration point and plays a crucial role in the pathogenesis of AKI, especially in cell apoptosis and proliferation. 2) GSK3β resides at the nexus of multiple signaling pathways implicated in the regulation of mitochondrial permeability transition (MPT), which upon injury, phosphorylated cyclophilin F in the mitochondria, sensitized MPT and eventually resulted in apoptosis. 3) Also GSK3β has been implicated in the regulation of cell proliferation. GSK3β is able to render phosphorylation of proproliferative molecules and initiate their ubiquitination and proteasomal degradation. Inhibition of GSK3β elevated expression of proproliferative molecules in renal tubular epithelia and accelerated recovery of renal function in AKI. 4) Moreover, blood levels of GSK3β was elevated in patients by the application of contrast media, accompanied by increased level of urinary KIM-1 and NAG enzyme, suggesting GSK3β plays a detrimental role in CI-AKI in the clinical setting. 5) Inhibition of GSK3β by lithium strikingly prevented cell injury induced by contrast media. Hence it is suggested GSK3β plays a key role in the pathogenesis of CI-AKI. This study is going to explore the role of GSK3β in CI-AKI in renal tubular cells acutely injured by the contrast media in both aspects of cell apoptosis and proliferation. The potential role and implication of GSK3β, the target of lithium, in contrast-induced nephropathy is delineated.

英文关键词： Acute kidney injury;Glycogen synthase kinase 3β ;Apoptosis;Cell proliferation ;Kidney repair