1] Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia [2] Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Collaborative Transplant Research Group, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Kidney Int. 2014 Apr;85(4):824-32. doi: 10.1038/ki.2013.475. Epub 2013 Dec 18.
A preconditioning effect occurs when exposure to a nonharmful quantity of a mediator of injury provides protection against injury upon subsequent reexposure. High-mobility group box 1 (HMGB1) protein, an endogenous ligand for Toll-like receptor (TLR) 4, is a TLR4-dependent mediator of kidney ischemia-reperfusion injury. Here we determined whether preconditioning with recombinant HMGB1 can block kidney ischemia-reperfusion injury, whether this effect is TLR4 dependent and, if so, how preconditioning downregulates TLR signaling. Wild-type mice pretreated with rHMGB1 before ischemia were protected against kidney ischemia-reperfusion injury, indicated by lower serum creatinine, less tubular damage, less tubulointerstitial neutrophil and macrophage infiltration, and less tubular epithelial cell apoptosis versus control mice. Gene expression of TLR-downstream cytokines and chemokines in ischemia-reperfusion injury kidney were also significantly reduced. While TLR4 and TLR2 knockout mice were protected against kidney ischemia-reperfusion injury, HMGB1 preconditioning provided additional protection to TLR2 but not TLR4 knockout mice. The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation, a negative regulator of HMGB1-mediated TLR4 pathway activation. Thus, preconditioning with rHMGB1 affords significant protection from TLR4-dependent kidney ischemia-reperfusion injury, indicating therapeutic potential.
预处理效应是指当暴露于非损伤性的损伤介质的适量时，会对随后的再暴露引起的损伤提供保护作用。高迁移率族蛋白 B1（HMGB1）蛋白是 Toll 样受体（TLR）4 的内源性配体，是肾缺血再灌注损伤的 TLR4 依赖性介质。在这里，我们确定了重组 HMGB1 的预处理是否可以阻断肾缺血再灌注损伤，这种作用是否依赖于 TLR4，如果是，预处理如何下调 TLR 信号。在缺血前用 rHMGB1 预处理的野生型小鼠对肾缺血再灌注损伤具有保护作用，表现在血清肌酐降低、肾小管损伤减少、肾小管间质中性粒细胞和巨噬细胞浸润减少以及肾小管上皮细胞凋亡减少，与对照组相比。缺血再灌注损伤肾脏中 TLR 下游细胞因子和趋化因子的基因表达也显著降低。虽然 TLR4 和 TLR2 敲除小鼠对肾缺血再灌注损伤具有保护作用，但 HMGB1 预处理为 TLR2 敲除小鼠提供了额外的保护作用，但对 TLR4 敲除小鼠没有。rHMGB1 预处理的保护作用涉及 Siglec-G 的上调，Siglec-G 是 HMGB1 介导的 TLR4 途径激活的负调节剂。因此，rHMGB1 的预处理可显著防止 TLR4 依赖性肾缺血再灌注损伤，表明其具有治疗潜力。
