过度的炎症反应是急性肾损伤（AKI）的重要特征，也是加剧肾损伤的关键。在众多炎症因子中，IL-18在AKI时升高最为显著，甚至可作为AKI的诊断指标。肾小管上皮细胞是AKI时肾损伤的关键部位，同时也是炎症因子的重要来源，而IL-18主要来源就是小管上皮。IL-18能通过激活FasL/Fas受体通路等多种方式加剧肾损伤。然而，由于IL-18缺乏细胞分泌的信号肽，正常情况下细胞并不具备分泌IL-18的能力，其分泌机制并未阐明。预实验结果显示，在AKI动物模型中GsdmD剪切增加，同时Caspase-11表达升高。基于前期观察，我们提出假说，AKI时caspase-11表达升高，通过剪切GsdmD，促使其N-端发生膜转位并形成膜孔，从而促进了肾小管上皮细胞IL-18释放。课题拟利用Caspase-11和GsdmD基因敲除小鼠建立的AKI模型，结合在培养的小管上皮细胞中研究对这一假说加以验证。

Acute renal injury (AKI) is characterized by rapid decline in renal filtration and release of inflammatory cytokines. Excessive inflammatory response is a key risk factor for accelerating renal injury. Among the different inflammatory cytokines, the increase of interlukin-18 (IL-18) is the most obvious and even accepted as a diagnostic indicator of AKI. Renal tubule is the major target of AKI. Meanwhile, renal tubular epithelial cell is also the major source of inflammatory cytokines. Release of IL-18 induces renal injury by activating FasL/Fas receptor pathway and NF-kB, promoting TNF-a, MCP-1 expression and microphage filtration. However, renal epithelial cell normally can not secret IL-18 since IL-18 is lack of secretory signal domain. In our preliminary study, we observed that the cleavage of GsdmD was increased, meanwhile, caspase-11 was also increased. Based on the preliminary observation, we hypothesized that under the pathological condition of AKI, the expression of caspase-11 is increased. Caspase-11 promotes the cleavage of GsdmD, initiates its translocation to the membrane and then facilitates the release of IL-18. The release of large amount of IL-18 from renal epithelial cells accelerates renal injury. We plan to test the hypothesis in caspase-11 and GsdmD gene knockout mice and cultured renal tubular epithelial cells. The result of the study will provide new evidence for understanding the molecular mechanism of renal injury and explore the new strategy for the treatment of AKI.