DFNB59调控AKI肾小管上皮细胞pyroptosis的作用及其机制研究

The proinflammatory cytokines, interleukin-1beta (IL-1β), interleukin-18 (IL-18), plays a major role in the cascade of inflammation that occurs in acute kidney injury (AKI). Understanding the exact mechnism of proinflammatory prevalent in AKI will facilitate identification of molecular targets for therapeutic intervention. Pyroptosis is characterized by rapid plasma membrane rupture and release of pro-inflammatory intracellular contents. Recently, gasdermin D (GSDMD), a DFNB59 homologous protein, was identified as an essential mediator of pyroptosis. However, the exact mechnism of how pyroptosis is regulated and how it is involed in the progression of AKI has not been fully elucidated. Our study found that renal tubular epithelial cells underwent pyroptosis to release of pro-inflammatory mediators in AKI, and Hypoxia-reoxygenation injury (HRI) caused an upregulation of DFNB59 in renal tubule epithelial cells, which was accompanied by increased levels of IL-1β in supernatants. Accordingly, we speculate that DFNB59 might trigger the pyroptosis of renal tubular epithelial cells in AKI. We plan to investigate the role and molecular mechanism of DFNB59-mediated pyroptosis of renal tubular epithelial cells in AKI and explore the critical role of DFNB59 and pyroptosis in renal tissue inflammation in vitro and in vivo experiments. The further step is to provide a new theoretical basis and intervention targets for inflammation in AKI.

肾小管上皮细胞来源的促炎症介质是引起AKI炎症反应瀑布最核心的病理生理基础。由于多重机制调控其产生与活化，因此在上述环节难以发现遏制AKI炎症反应的理想靶点。Pyroptosis是细胞促炎症介质释放的主要途径，但在AKI炎症反应中的作用及调控机制尚不清楚。我们首次证实，AKI时肾小管上皮细胞发生了pyroptosis，并发现DFNB59与肾小管上皮细胞pyroptosis密切相关。新近研究证实，DFNB59的同源蛋白GSDMD是触发免疫细胞pyroptosis的分子开关。本课题将证实DFNB59是触发肾小管上皮细胞pyroptosis的分子开关，并阐明其调控机制；进一步利用条件特异性DFNB59基因敲除小鼠，揭示DFNB59触发的pyroptosis在促进AKI炎症反应和疾病进展中的重要作用。从而为探索有效遏制AKI炎症反应的策略提供了全新的理论基础。