Yu X Q, Fan J M, Nikolic-Paterson D J, Yang N, Mu W, Pichler R, Johnson R J, Atkins R C, Lan H Y
Department of Nephrology, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.
Am J Pathol. 1999 Mar;154(3):833-41. doi: 10.1016/S0002-9440(10)65330-8.
Osteopontin (OPN) is a macrophage chemotactic and adhesion molecule that acts to promote macrophage infiltration in rat anti-glomerular basement membrane (GBM) glomerulonephritis. The present study investigated the role of interleukin-1 (IL-1) in the up-regulation of renal OPN expression in this disease model. Accelerated anti-GBM glomerulonephritis was induced in groups of six rats. Animals were treated by a constant infusion of the IL-1 receptor antagonist or saline (control) over days -1 to 14 (induction phase) or days 7 to 21 (established disease). In normal rat kidney, OPN was expressed in a few tubules (<5%) and absent from glomeruli. During the development of rat anti-GBM disease (days 7 to 21), there was substantial up-regulation of OPN mRNA and protein expression in glomeruli (>5 cells per glomerular cross-section) and tubular epithelial cells (50-75% OPN-positive). Up-regulation of OPN expression was associated with macrophage accumulation within the kidney, severe proteinuria, loss of renal function, and severe histological damage including glomerular crescentic formation and tubulointerstitial fibrosis. In contrast, IL-1 receptor antagonist treatment of either the induction phase of disease or established disease significantly reduced OPN mRNA and protein expression in glomeruli (/75-85%, P < 0.001) and tubules (/45-60%, P < 0.001). The reduction in OPN expression was associated with significant inhibition of macrophage accumulation and progressive renal injury. In vitro, the addition of IL-1 to the normal rat tubular epithelial cell line NRK52E up-regulated OPN mRNA and protein levels, an effect that was dose-dependent and inhibited by the addition of IL-1 receptor antagonist, thus demonstrating that IL-1 can act directly to up-regulate renal OPN expression. In conclusion, this study provides in vivo and in vitro evidence that IL-1 up-regulates OPN expression in experimental kidney disease and support for the argument that inhibition of OPN expression is one mechanism by which IL-1 receptor antagonist treatment suppresses macrophage-mediated renal injury.
骨桥蛋白（OPN）是一种巨噬细胞趋化和黏附分子，在大鼠抗肾小球基底膜（GBM）肾小球肾炎中可促进巨噬细胞浸润。本研究调查了白细胞介素-1（IL-1）在该疾病模型中肾OPN表达上调中的作用。对每组6只大鼠诱导出加速性抗GBM肾小球肾炎。在第-1天至14天（诱导期）或第7天至21天（疾病已形成期），通过持续输注IL-1受体拮抗剂或生理盐水（对照）对动物进行治疗。在正常大鼠肾脏中，OPN在少数肾小管中表达（<5%），肾小球中无表达。在大鼠抗GBM疾病发展过程中（第7天至21天），肾小球（每个肾小球横截面>5个细胞）和肾小管上皮细胞（50 - 75% OPN阳性）中OPN mRNA和蛋白表达显著上调。OPN表达上调与肾脏内巨噬细胞积聚、严重蛋白尿、肾功能丧失以及严重组织学损伤有关，包括肾小球新月体形成和肾小管间质纤维化。相比之下，在疾病诱导期或疾病已形成期给予IL-1受体拮抗剂治疗，可显著降低肾小球（/75 - 85%，P < 0.001）和肾小管（/45 - 60%，P < 0.001）中OPN mRNA和蛋白表达。OPN表达降低与巨噬细胞积聚和进行性肾损伤的显著抑制有关。在体外，向正常大鼠肾小管上皮细胞系NRK52E中添加IL-1可上调OPN mRNA和蛋白水平，该效应呈剂量依赖性，并可被添加IL-1受体拮抗剂所抑制，从而表明IL-1可直接作用上调肾OPN表达。总之，本研究提供了体内和体外证据，证明IL-1在实验性肾脏疾病中上调OPN表达，并支持以下观点：抑制OPN表达是IL-1受体拮抗剂治疗抑制巨噬细胞介导的肾损伤的一种机制。
