Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis,Cell Biology and Toxicology

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Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-07-02 , DOI: 10.1007/s10565-021-09622-z
Jiarui Han _{1,

2} , Zhenkui Zuo _{1,

3} , Xiujie Shi _{1,

2} , Yage Zhang _{1,

2} , Zining Peng _{1,

2} , Yufeng Xing _{1,

2} , Xinxin Pang _{1,

2}

Affiliation

Our group previously reported that hirudin ameliorated diabetic nephropathy (DN) in streptozotocin (STZ)-injected rats, but the mechanism remained largely unknown. Therefore, we further explored its possible mechanism. We subcutaneously injected 5 U hirudin into STZ-induced WT mice or Gasdermin D (Gsdmd)^−/− (KO) mice daily for 12 weeks, respectively, and evaluated their kidney injury. Next, glomerular endothelial cells (GECs), renal tubular epithelial cells (RTECs), and bone-marrow-derived macrophages (BMDMs) were isolated from WT mice and treated with hirudin in the presence of high glucose/lipopolysaccharides and ATP to measure the release of interleukin-18 and interleukin-1β. Kidney injury induced by STZ injection was significantly ameliorated by hirudin through inhibiting Gsdmd-mediated pyroptosis in the mice, not Caspase 1-mediated apoptosis. Meanwhile, hirudin also suppressed pyroptosis in primary GECs, RTECs, and BMDMs in vitro. Moreover, the deletion of Gsdmd reduced pyroptosis and kidney injury both in vivo and in vitro. We also found that hirudin regulated the expression of Gsdmd by inhibiting interferon regulatory factor 2 (Irf2). Hirudin ameliorated Gsdmd-mediated pyroptosis by inhibiting irf2, leading to the improvement of kidney injury. Therefore, hirudin might serve as a potential therapeutic strategy to treat DN.

Graphical abstract

中文翻译：

水蛭素通过抑制 Gsdmd 介导的细胞焦亡改善糖尿病肾病

我们的研究小组之前曾报道，水蛭素可改善注射链脲佐菌素（STZ）的大鼠的糖尿病肾病（DN），但其机制仍不清楚。因此，我们进一步探讨了其可能的机制。^{我们分别向 STZ 诱导的 WT 小鼠或 Gasdermin D (Gsdmd) −/−} (KO) 小鼠皮下注射 5 U 水蛭素，持续 12 周，并评估其肾损伤。接下来，从 WT 小鼠中分离肾小球内皮细胞 (GEC)、肾小管上皮细胞 (RTEC) 和骨髓源性巨噬细胞 (BMDM)，并在高葡萄糖/脂多糖和 ATP 存在下用水蛭素处理以测量释放情况白细胞介素 18 和白细胞介素 1β。水蛭素通过抑制 Gsdmd 介导的小鼠细胞焦亡，而非 Caspase 1 介导的细胞凋亡，显着改善 STZ 注射引起的肾损伤。同时，水蛭素还在体外抑制原代GEC、RTEC和BMDM的细胞焦亡。此外，Gsdmd 的缺失在体内和体外均减少了细胞焦亡和肾损伤。我们还发现水蛭素通过抑制干扰素调节因子2（Irf2）来调节Gsdmd的表达。水蛭素通过抑制 irf2 改善 Gsdmd 介导的细胞焦亡，从而改善肾损伤。因此，水蛭素可能作为治疗 DN 的潜在治疗策略。

图形概要

更新日期：2021-07-02

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