Abstract
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.
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Funding
The study was supported by the Henan Province Science and Technology Research Project (202102310171); Henan Province Special Key Project of Traditional Chinese Medicine Scientific Research (20-21zy1003); Henan Province top-notch personnel training project of traditional Chinese medicine; national backbone personnel training project of traditional Chinese medicine innovation.
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Study design, manuscript preparation: Zhenkui Zuo and Xinxin Pang. Literature search, data collection, statistical analysis, data interpretation: Jiarui Han, Zhenkui Zuo, Xiujie Shi, Yage Zhang, Zining Peng, Yufeng Xing, and Xinxin Pang.
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Han, J., Zuo, Z., Shi, X. et al. Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis. Cell Biol Toxicol 39, 573–589 (2023). https://doi.org/10.1007/s10565-021-09622-z
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DOI: https://doi.org/10.1007/s10565-021-09622-z