Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway.
Disulfiram ameliorates ischemia/reperfusion-induced acute kidney injury by suppressing the caspase-11-GSDMD pathway.
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DOI：
10.1080/0886022x.2022.2098764
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发表时间：
2022-12
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影响因子：
3
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中科院分区：
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急性肾损伤（阿基）是一种严重的疾病，死亡率高。最常见的原因是肾缺血/再灌注（IR）损伤，这被认为是密切相关的焦亡。双硫仑是一种众所周知的酒精滥用药物，最近的研究表明其能够减轻小鼠巨噬细胞的焦亡。本研究旨在探讨双硫仑是否能改善IR诱导的阿基，并阐明其可能的分子机制。我们建立了小鼠肾脏IR模型和小鼠肾小管上皮细胞（MTEC）缺氧/复氧（HR）损伤模型。结果表明，IR可引起小鼠肾功能损害，并引发肾小管上皮细胞的焦亡，双硫仑可改善IR后的肾功能损害。（核苷酸结合寡聚结构域（NOD）样受体蛋白3（NLRP 3）、凋亡相关特异性蛋白（ASC）、半胱天冬酶-1、N-GSDMD）和非经典的细胞凋亡途径双硫仑阻断了非经典的但不是所有经典的细胞凋亡途径蛋白（NLRP 3和ASC）的上调，表明双硫仑可能通过抑制caspase-11-GSDMD途径来减少细胞凋亡。在体外实验中，HR可使MTECs细胞内ROS水平、PI染色阳性率和LDH水平升高，双硫仑可逆转HR的上述作用。此外，我们进行了计算机模拟的TIR结构域的TLR 4同源建模，并确定了一个小分子之间的结合能双硫仑和TIR结构域。结论双硫仑可能通过拮抗TLR 4和抑制caspase-11-GSDMD途径抑制细胞凋亡。
Acute kidney injury (AKI) is a serious condition with high mortality. The most common cause is kidney ischemia/reperfusion (IR) injury, which is thought to be closely related to pyroptosis. Disulfiram is a well-known alcohol abuse drug, and recent studies have shown its ability to mitigate pyroptosis in mouse macrophages. This study investigated whether disulfiram could improve IR-induced AKI and elucidated the possible molecular mechanism. We generated an IR model in mouse kidneys and a hypoxia/reoxygenation (HR) injury model with murine tubular epithelial cells (MTECs). The results showed that IR caused renal dysfunction in mice and triggered pyroptosis in renal tubular epithelial cells, and disulfiram improved renal impairment after IR. The expression of proteins associated with the classical pyroptosis pathway (Nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3), apoptosis-related specific protein (ASC), caspase-1, N-GSDMD) and nonclassical pyroptosis pathway (caspase-11, N-GSDMD) were upregulated after IR. Disulfiram blocked the upregulation of nonclassical but not all classical pyroptosis pathway proteins (NLRP3 and ASC), suggesting that disulfiram might reduce pyroptosis by inhibiting the caspase-11-GSDMD pathway. In vitro, HR increased intracellular ROS levels, the positive rate of PI staining and LDH levels in MTECs, all of which were reversed by disulfiram pretreatment. Furthermore, we performed a computer simulation of the TIR domain of TLR4 using homology modeling and identified a small molecular binding energy between disulfiram and the TIR domain. We concluded that disulfiram might inhibit pyroptosis by antagonizing TLR4 and inhibiting the caspase-11-GSDMD pathway.