Wang Yiping, Mahajan Deepika, Tay Yuet-Ching, Bao Shisan, Spicer Tim, Kairaitis Lukas, Rangan Gopala K, Harris David C H
Department of Renal Medicine, The University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales, Australia.
Nephrology (Carlton). 2005 Oct;10(5):470-7. doi: 10.1111/j.1440-1797.2005.00438.x.
Because macrophages are considered to be possible effectors of disease in Adriamycin (ADR) nephrosis, we hypothesized that depletion of macrophages might protect against the initiation of renal injury. In the present study, a monoclonal antibody (ED7) directed against CD11b/CD18 integrin, which is expressed by macrophages, was used to investigate the pathogenetic effects of macrophages in ADR nephropathy.
Male Wistar rats were treated with ED7 antibody, starting 1 day prior to ADR (7.5 mg/kg) treatment, or 7 days post-ADR when overt proteinuria was established.
Circulating ED7-positive cells were reduced by approximately 30% in rats with ADR nephrosis by the ED7 antibody, while the number of macrophages in the renal cortex of ADR rats was reduced by nearly 50% with the ED7 treatment, whether administered before or after ADR. Creatinine clearance was significantly ameliorated by ED7 when commenced pre-ADR (P < 0.05), but not when commenced post-ADR (P = NS) in comparison to untreated ADR rats. However, proteinuria was not alleviated by either ED7 treatment. Morphometric analysis showed less glomerular sclerosis when ED7 was commenced pre-ADR compared with ADR alone (P < 0.01), but not when commenced post-ADR (P = NS). Tubular atrophy was reduced by ED7 when it was commenced pre-ADR (tubular cell height and tubular diameter: P < 0.01 and P < 0.001, respectively), as was interstitial expansion (P < 0.01) compared with ADR alone. Cortical macrophage infiltration was reduced by 50% compared with ADR alone by the ED7 commenced before or after ADR. The number of cortical CD4+ T cells fell with ED7 starting pre-ADR, but not with the ED7 treatment commencing after ADR.
Partial macrophage depletion starting before but not after ADR protected both renal function and structure in this model of chronic proteinuric renal disease.
由于巨噬细胞被认为是阿霉素（ADR）肾病中疾病的可能效应细胞，我们推测巨噬细胞的耗竭可能预防肾损伤的起始。在本研究中，一种针对巨噬细胞表达的CD11b/CD18整合素的单克隆抗体（ED7）被用于研究巨噬细胞在ADR肾病中的致病作用。
雄性Wistar大鼠在ADR（7.5mg/kg）治疗前1天或在明显蛋白尿形成后的ADR治疗后7天开始用ED7抗体治疗。
用ED7抗体治疗的ADR肾病大鼠中循环ED7阳性细胞减少约30%，而无论在ADR之前还是之后给予ED7治疗，ADR大鼠肾皮质中的巨噬细胞数量减少近50%。与未治疗的ADR大鼠相比，ADR之前开始使用ED7时肌酐清除率显著改善（P<0.05），但ADR之后开始使用时则无改善（P=无显著性差异）。然而，两种ED7治疗均未减轻蛋白尿。形态计量分析显示，与单独使用ADR相比，ADR之前开始使用ED7时肾小球硬化较少（P<0.01），但ADR之后开始使用时则无差异（P=无显著性差异）。ADR之前开始使用ED7时肾小管萎缩减轻（肾小管细胞高度和肾小管直径：分别为P<0.01和P<0.001），与单独使用ADR相比，间质扩张也减轻（P<0.01）。与单独使用ADR相比，ADR之前或之后开始使用ED7时皮质巨噬细胞浸润减少50%。ADR之前开始使用ED7时皮质CD4+T细胞数量下降，但ADR之后开始ED7治疗时则未下降。
在该慢性蛋白尿性肾病模型中，在ADR之前而非之后开始部分巨噬细胞耗竭可保护肾功能和结构。
