ALR通过STAT3/System Xc- 途径对急性肾损伤中铁死亡的干预作用及机制研究

Acute kidney injury (AKI) is a common and severe renal disease characterized by high morbidity and mortality. Recent studies have found that ferroptosis of renal tubular epithelial cell was involved in AKI .However, the mechanism remains to be clarified at present . The essence of ferroptosis is metabolic disorder of lipid oxide, thus lipid peroxides can not get through GSH metabolism catalyzed by GPX4, which produces a large amount of toxic lipid ROS. Morever, the decrease in the activity of System Xc- induced aboundant accumulation ROS is the key to trigger ferroptosis. STAT3 could negatively regulate System Xc- expression recently. . Our preliminary data revealed that Augmenter of liver regeneration(ALR) has protective effect on acute kidney injury by inhibiting apoptosis and regulating autophagy in renal tubular epithelial cell .We also found that ALR has a protective effect on AKI by ameliorating the production of ROS. However, the mechanism is blurred. ALR could regulate STAT3. We also found that renal tubular epithelial cell could cause more severe ferroptosis through interfering ALR expression. So, We suggest that ALR shows protective effect on ferroptosis through regulates System Xc- mediated cystine metabolism by STAT3 signal pathway.

急性肾损伤（AKI）是临床常见的危急症，有较高的发病率和病死率。最近研究发现肾小管上皮细胞（RTEC）铁死亡是AKI的重要发病机制，但有待进一步阐明。铁死亡的本质是谷胱甘肽过氧化物酶4（GPX4）活性下降，造成脂质活性氧（ROS）的积累导致细胞死亡。胱氨酸/谷氨酸反向转运体（System Xc-）通道是调节GPX4活性的关键，STAT3可以负向调控System Xc-的活性。 . 我们前期研究发现肝再生增强因子（ALR）具有促进RTEC增殖、抑制RTEC凋亡的作用；同时发现ALR可以抑制RTEC产生ROS，但具体机制不清楚。我们最近发现体外干扰ALR的表达可以加重RTEC铁死亡，而ALR对STAT3具有调控作用，因此，我们提出科学假说：ALR可能通过干预RTEC铁死亡而对AKI发挥肾保护作用，其作用途径可能与ALR抑制STAT3的表达，从而调控System Xc-介导的胱氨酸代谢有关。

急性肾损伤（AKI）是临床常见的急危重症，有较高的发病率和病死率。最近研究发现肾小管上皮细胞铁死亡是AKI的重要发病机制，但有待进一步阐明。我们的研究从临床、体内、体外实验三方面入手，全面探讨了肝再生增强因子（ALR）对缺血再灌注（I/R）导致AKI中肾小管上皮细胞中的保护作用及作用机制。我们发现，ALR参与了I/R导致的AKI中肾小管上皮细胞的铁死亡，通过构建肾小管上皮细胞特异性敲除ALR的小鼠（PT-ALR），复制缺血再灌注AKI模型，发现肾小管上皮细胞特异性敲除ALR后，加剧了缺血再灌注导致的AKI的病理损伤及肾功能异常。同时，我们通过铁死亡的表型检测，发现特异性敲除肾脏肾小管细胞ALR后，铁死亡明显加重；肾小管线粒体形态学显示线粒体嵴减少，甚至断裂，线粒体基质颜色加深。体外实验通过缺氧复氧复制体内AKI模型，构建过表达ALR的慢病毒转染肾小管上皮细胞，发现过表达ALR能够减轻缺氧复氧对肾小管上皮细胞的损伤及铁死亡，并探讨了其作用机制。我们的研究为进一步深入阐明I/R急性肾损伤的发病机制、寻求AKI新的治疗方法奠定了科学基础。