MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Kidney Int. 2012 Oct;82(8):928-33. doi: 10.1038/ki.2012.207. Epub 2012 Jun 6.
The role of resident renal mononuclear phagocytes in acute kidney injury is controversial with experimental data suggesting both deleterious and protective functions. To help resolve this, we used mice transgenic for the human diphtheria toxin receptor under the control of the CD11b promoter and treated them with diphtheria toxin, or liposomal clodronate, or both to deplete monocyte/mononuclear phagocytes prior to renal ischemia/reperfusion injury. Although either system effectively depleted circulating monocytes and resident mononuclear phagocytes, depletion was most marked in diphtheria toxin-treated mice. Despite this, diphtheria toxin treatment did not protect from renal ischemia. In contrast, mice treated with clodronate exhibited reduced renal failure and acute tubular necrosis, suggesting key differences between these depletion strategies. Clodronate did not deplete CD206-positive renal macrophages and, unlike diphtheria toxin, left resident CD11c-positive cells unscathed while inducing dramatic apoptosis in hepatic and splenic mononuclear phagocyte populations. Abolition of the protected phenotype by administration of diphtheria toxin to clodronate-treated mice suggested that the protective effect of clodronate resulted from the presence of a cytoprotective intrarenal population of mononuclear phagocytes sensitive to diphtheria toxin-mediated ablation.
驻留于肾脏的单核吞噬细胞在急性肾损伤中的作用存在争议，实验数据表明其具有有害和保护双重功能。为了帮助解决这一问题，我们使用了 CD11b 启动子控制下的人白喉毒素受体转基因小鼠，并在肾缺血/再灌注损伤前用白喉毒素、脂质体氯膦酸盐或两者联合处理，以耗尽单核细胞/单核吞噬细胞。虽然这两种系统都能有效地耗尽循环单核细胞和驻留的单核吞噬细胞，但白喉毒素处理组的耗竭最为明显。尽管如此，白喉毒素处理并不能保护肾脏免受缺血损伤。相比之下，用氯膦酸盐处理的小鼠表现出肾功能衰竭和急性肾小管坏死的减少，表明这两种耗竭策略之间存在关键差异。氯膦酸盐并没有耗尽 CD206 阳性的肾脏巨噬细胞，与白喉毒素不同，它没有损伤驻留的 CD11c 阳性细胞，同时诱导肝脏和脾脏单核吞噬细胞群体发生剧烈的细胞凋亡。在氯膦酸盐处理的小鼠中给予白喉毒素后，保护性表型被消除，这表明氯膦酸盐的保护作用源于对肾内对白喉毒素介导的消融敏感的保护性单核吞噬细胞群体的存在。
