lncRNA343/miR-509-3p/STC1轴在CI-AKI肾小管上皮细胞线粒体质量控制失衡中的作用与机制

The pathogenic mechanism of iodinated contrast-induced acute kidney injury (CI-AKI) is mainly associated with direct nephrotoxicity, renal ischemia and oxidative stress. Previous studies found that the imbalance of mitochondrial quality control (excessive ROS generation, mitochondrial damage and mitophagy) plays an important role in apoptosis induced by iodinated contrast media, however, the detail mechanism remain unknown. The regulatory mechanisms of lncRNA on mitochondrial quality control is a hot topic in cell biology research. By RNA-seq and realtime PCR, our pretests demonstrate that the expression of lncRNA343 and SCT1 were downregulated in CI-AKI kidney tissue, while miR-509-3p was upregulated. We also found that STC1 inhibited mitochondrial ROS generation and attenuate cytotoxicity, suggesting that“lncRNA343-miR-509-3p-STC1” might involve in the development of CI-AKI by regulating mitochondrial quality control. In the project, we use the previously-established CI-AKI animal model and cell model and focus on determining the role of lncRNA343 in iodinated contrast media-induced acute kidney injury; exploring the mechanisms of the above regulatory network of“lncRNA343-miR-509-3p-STC1” on mitochondrial quality control in CI-AKI. Therefore, the overall goal of this study is to reveal the new pathogenesis of CI-AKI, so as to provide a novel therapeutic strategy for CI-AKI.

碘造影剂急性肾损伤（CI-AKI）主要与肾毒性、肾缺血和氧化应激有关。我们前期研究发现线粒体质量控制失衡（活性氧增多、线粒体损伤和线粒体自噬）在碘造影剂致肾小管上皮细胞凋亡中起重要作用，但机制尚不清楚。lncRNA对调节线粒体质量控制的作用是目前细胞生物学的研究热点。我们预实验已证实lncRNA343在CI-AKI大鼠肾组织中的表达降低，其靶分子miRNA-509-3p表达上调，同时下游靶基因斯钙素1(STC1)表达下降；STC1可抑制线粒体活性氧产生，减少细胞凋亡；我们推测lncRNA343-miRNA-509-3p-STC1轴通过调节线粒体质量控制对CI-AKI起关键作用。本课题采用转基因大鼠及细胞分子生物学方法从体内体外两个层面研究lncRNA343在CI-AKI中的作用，探讨上述调控网络对线粒体质量控制的相关机制，旨在揭示CI-AKI发病新机制，从而为防治CI-AKI提供新的靶点。

碘造影剂急性肾损伤（CI-AKI）已成为医源性急性肾损伤最常见的原因之一。目前认为碘造影剂主要通过改变肾脏血流动力学和/或直接作用于肾小管上皮细胞导致细胞损伤和死亡，引起肾脏损伤。线粒体质量控制失衡在碘造影剂致肾小管上皮细胞凋亡中起重要作用，但机制尚不清楚。本项目主要围绕以下8个问题展开研究：1、研究了lncRNA343、miR−509−3p和 Stanniocalcin-1 (STC1) 在CI-AKI肾组织表达水平及其与急性肾脏损伤和肾小管上皮损伤的相互关系；2、探讨了STC1对CI-AKI的保护作用及其对线粒体质量控制的调控机制；3、发现了碘造影剂急性肾损伤患者血清的lncRNA和mRNA表达谱改变；4、基于深度神经网络开发和验证了住院慢性肾脏病患者静脉碘造影后AKI发生的预测模型；5、研究了静脉碘造影对住院AKI患者预后的影响；6、建立了住院AKI患者急性肾脏病的流行病学和预警模型；7、针对不同群体建立了住院AKI患者的预后预测模型；8、系统评价了间充质干细胞在动物试验与临床试验中对肾血管疾病的疗效。总之，本项目初步揭示了lncRNA343与大鼠肾功能及肾组织损伤程度呈负相关，证实了STC1通过 Nrf2 通路调节线粒体质量控制保护碘造影剂急性肾损伤，在本项目的资助下，本课题组在Nephrology Dialysis Transplantation、European Radiology等杂志发表高水平研究成果16篇，培养3名硕士研究生、7名博士研究生（5名将于2023年毕业，2名已工作）。参与国际与国内学术会议各1次，口头报告论文4篇。