IRE1/JNK信号通路在急性肾损伤中调控肾小管上皮细胞炎性因子分泌及对系膜细胞损伤的机制研究

Acute kidney injury (AKI) is a common yet life-threatening disease. Recent observations indicate that sustained and repeated insults in AKI eventually cause glomerular sclerosis and chronic kidney disease. Although inflammation plays a critical role in the progression of the disease, the detailed mechanism remains largely unknown. . Previous sudies suggest that the IRE1 / JNK pathway regulate the production of proinflammatory factors in different types of the tissues. Consistently, our preliminary data showed that AKI induced the secretions of a large number of inflammatory cytokines in renal tubular epithelial cells, leading to the damages of mesangial cells and increased production of mesangial matrix. . Based on these findings, we hypothesized that IRE1/JNK signaling pathway upregulate the production of inflammatory cytokines in renal tubular epithelial cells in AKI, and that the damages of mesangial cells and the progression of glomerular sclerosis ensue. . To test our hypotheses, we will establish a mouse model of ischemia-reperfusion injury and an in vitro model of hypoxia-reoxygenation injury in cells. In addition, we will silence certain genes using a lentiviral infection system. The results will be assessed with different methods including electron microscopy, immunohistochemistry, and molecular biology techniques. The present project aimes to, from the levels of molecular, subcellular, cellular, tissue, and animal, unveil the effect of inflammatory factors from the renal tubular epithelial cells on the damage of mesangial cells in AKI, and to explore the detailed mechanisms underlying such damages. From the perspective of inflammatory responses, these stuides may lend novel insight to the mechanism of AKI-related glomerular sclerosis, and help find some new therapeutic targets for the prevention of AKI progression.

急性肾损伤（AKI）是一种高发病率、高死亡率的临床常见急危重症。近来认为AKI持续存在、反复发生可导致肾小球硬化、向慢性肾脏病进展。在此过程中炎症反应起了重要作用，但机制不清楚。有报道IRE1/JNK通路在多种组织介导炎性因子产生。我们的预实验结果提示AKI可使肾小管上皮细胞产生大量炎性因子，并导致系膜细胞损伤、系膜基质增生。据此我们假设：AKI中IRE1/JNK通路可能调控肾小管上皮细胞炎性因子的分泌，并损伤系膜细胞，促进肾小球硬化。本项目拟用缺血再灌注小鼠模型、缺氧复氧细胞模型，采用基因敲除慢病毒感染系统、电镜技术、免疫组化、分子生物学技术等手段，从分子、亚细胞、细胞、组织以及动物整体水平等多方面明确炎性因子在AKI中调控肾小管上皮细胞对系膜细胞损伤的作用，探讨损伤机制。本研究将从炎症反应的角度为揭示AKI导致肾小球硬化的发生机制奠定基础，为防止AKI进展提供新思路。

急性肾损伤（AKI）是一种高发病率、高死亡率的临床常见急危重症。AKI持续存在、反复发生可导致肾小球硬化、向慢性肾脏病进展。在此过程中炎症反应起了重要作用，但机制不清楚。我们的研究显示缺血再灌注肾损伤可使肾小管上皮细胞发生内质网应激，IRE1/JNK通路激活，产生大量炎性因子，随后导致系膜细胞损伤、系膜基质增生，细胞外基质增多，进而导致肾小球硬化的发生。本项目用缺血再灌注小鼠模型、缺氧复氧细胞模型，采用基因敲除慢病毒感染系统、电镜技术、免疫组化、分子生物学技术等手段，从分子、亚细胞、细胞、组织以及动物整体水平等多方面明确炎性因子在AKI中调控肾小管上皮细胞对系膜细胞损伤的作用，探讨损伤机制。本研究将从炎症反应的角度揭示AKI导致肾小球硬化的发生机制，为防止AKI进展提供了新思路。