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.