Lan H Y, Yang N, Nikolic-Paterson D J, Yu X Q, Mu W, Isbel N M, Metz C N, Bucala R, Atkins R C
Department of Nephrology, Monash Medical Center, Clayton, Victoria, Australia.
Kidney Int. 2000 Feb;57(2):499-509. doi: 10.1046/j.1523-1755.2000.00869.x.
We have recently demonstrated that macrophage migration inhibitory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in human GN.
MIF expression was examined by in situ hybridization and immunohistochemistry staining in 65 biopsies from a variety of glomerulonephridities.
There is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern of MIF expression in nonproliferative forms of GN such as minimal change disease and membranous GN. However, there was a marked increase in both glomerular and tubular MIF expression in proliferative forms of GN, including focal segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell infiltrate in these diseases were largely restricted to areas with marked up-regulation of MIF expression, contributing to glomerular hypercellularity, glomerular focal segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De novo MIF expression was evident in glomerular endothelial cells and mesangial cells in proliferative forms of GN. In addition, many infiltrating macrophages and T cells showed MIF mRNA and protein expression. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatinine clearance.
Renal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histologic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic target in the treatment of progressive forms of GN.
我们最近证实巨噬细胞移动抑制因子（MIF）在实验性肾小球肾炎（GN）中发挥致病作用。本研究旨在调查MIF在人类GN中的表达情况。
通过原位杂交和免疫组化染色检测了65份来自各种肾小球肾炎的活检标本中MIF的表达。
正常人类肾脏中存在MIF mRNA和蛋白的组成性表达，主要局限于肾小管上皮细胞和一些肾小球上皮细胞。在非增殖性GN形式如微小病变肾病和膜性GN中，MIF表达模式变化不大。然而，在增殖性GN形式中，包括局灶节段性肾小球硬化（FGS）、狼疮性肾炎、新月体性GN和系膜毛细血管增生性GN，肾小球和肾小管MIF表达均显著增加。这些疾病中突出的巨噬细胞和T细胞浸润主要局限于MIF表达明显上调的区域，导致肾小球细胞增多、肾小球局灶节段性病变、新月体形成、肾小管炎和肉芽肿性病变。在增殖性GN形式中，肾小球内皮细胞和系膜细胞中可见MIF的从头表达。此外，许多浸润的巨噬细胞和T细胞显示MIF mRNA和蛋白表达。定量分析发现，肾小球和肾小管MIF表达增加与巨噬细胞和T细胞积聚、组织学病变严重程度以及肌酐清除率降低高度相关。
在人类增殖性GN形式中，肾脏MIF表达明显上调，这与白细胞浸润、组织学损伤和肾功能损害相关。这些结果表明，MIF可能是人类进行性GN形式中肾损伤的重要介质。基于这些发现，结合MIF在实验性GN中已知的致病作用，我们提出MIF是治疗进行性GN形式的一个有吸引力的治疗靶点。
