Gasdermin家族蛋白介导的细胞程序性坏死在急性肾衰竭中的作用

Acute Renal Failure (ARF), now referred to as Acute Kidney Injury (AKI), is a common and clinically important problem. AKI frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). However, the molecular mechanisms of ATN under elucidated. Recently, we observed that GSDMD-mediated Pyroptosis signaling pathway contributed a key role to the Cisplatin-induced AKI. GSDMD belongs to a large gasdermin family bearing a novel membrane pore-forming activity. Pyroptosis is lytic, featuring cell swelling and large bubbles blowing from the plasma membrane, refers to the other form of programmed necrosis. This study, we aimed to investigate the function and the molecular mechanisms of Gasdermin mediated Pyroptosis signaling pathway in CLP-induced septic-AKI, and cisplatin-induced AKI. Furtherly, we screen a specific inhibitor for GSDMD, then combined this inhibitor with Necrostain-1 to intervene AKI in mice, aiming to discovery an efficiency therapeutic target of AKI.

急性肾衰竭（Acute Renal Failure，ARF），通常指Acute Kidney Injury(AKI)，发病率和致死率居高不下，严重威胁人类生命健康，探究ARF发病进程中隐藏的分子机制具有重要意义。临床上，ARF的诱因复杂而多样，急性肾小管坏死（Acute Tubular Necrosis，ATN）是其中最关键性因素之一。ATN的分子机制一直以来是人们的研究重点，我们近期的研究表明GSDMD介导的肾小管上皮细胞焦亡在Cisplatin-AKI中起着重要作用。本项目拟通过建立脓毒血症-AKI和Cisplatin-AKI模型，探究Gasdermin介导的细胞焦亡在AKI中的作用以及分子机制；并进一步筛选GSDMD特异性抑制剂，然后将该抑制剂与程序性细胞坏死抑制剂(Necrostain-1)联合用于小鼠AKI的干预，为临床上防治AKI提供一个行之有效的手段。

本项目中我们首先系统分析了Gasdermins家族蛋白在肾脏中的表达，发现Gsdmd/c/e是有表达的，Gsdma不表达。然后构建了一系列的基因敲除老鼠，较为全面地探讨了Gasdermins在AKI中的作用。其中Gsdma不参与AKI，Gsdmc对于顺铂诱导的AKI有些许贡献。Gsdme主要参与梗阻性肾损伤。特别地，我们发现Gsdmd介导的细胞焦亡是AKI的一个重要因素，Ripk3/Gsdmd双敲的小鼠实验表明同时阻断Ripk3介导的细胞坏死和Gsdmd介导的细胞焦亡对AKI的干预具有重要意义。我们还初步筛选到了2个活性较好的Gsdmd的抑制剂。另外，发现持续性激活p38信号通路参与了Gasdermins的转录表达，进而参与AKI。