Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy
Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy
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DOI：
10.1046/j.1523-1755.2000.00830.x
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发表时间：
2000-01-01
影响因子：
19.6
通讯作者：
Egido, J
中科院分区：
文献类型：
--
作者：
Mezzano, SA;Droguett, MA;Egido, J
背景。蛋白尿在肾小球疾病的进展中起着核心作用，越来越多的证据表明，蛋白尿可能通过释放趋化因子和纤维化因子来决定小管细胞的活化，从而导致间质炎症反应。然而，关于这一主题的大多数研究都是在实验模型中进行的，并且在人体肾脏活检方面的经验很少。我们分析了特发性膜性肾病（IMN）患者的组织切片，IMN是一种非炎症性肾小球疾病，可能伴随有重度持续性蛋白尿、间质细胞浸润和肾功能下降的进行性疾病。通过免疫组化[单核细胞趋化蛋白-1 (MCP-1)，激活正常t细胞表达和分泌的趋化因子（RANTES）、骨桥蛋白（OPN）、血小板衍生生长因子-be (PD-GF-BB)]和原位杂交[MCP-1、RANTES、PDGF-BB、转化生长因子- β 1 (tgf - β 1)]对25例IMN患者（13例进展性和12例非进展性）的石蜡包埋活检标本进行回顾性研究。此外，我们研究了肌成纤维细胞的存在，通过α -平滑肌肌动蛋白（α - sma）、单核/巨噬细胞（cd68阳性细胞）和t细胞浸润（CD4+和CD8+细胞）的表达来鉴定。所有患者在活检时均为肾病且未接受治疗。MCP-1、RANTES和OPN的表达显著上调，主要在小管上皮细胞中，且在进行性IMN患者中显著上调。我们注意到mRNA的表达与相应的蛋白之间有很强的相关性。这些趋化因子和OPN的存在与间质细胞浸润有关。tgf - β和PDGF也上调，主要在小管上皮细胞中，在进行性IMN中表达更强，并且与肌成纤维细胞的存在有关。严重蛋白尿和进行性IMN患者在小管上皮细胞中过度表达趋化因子MCP-1、RANTES和OPN以及促纤维化细胞因子PDGF-BB和tgf - β。由于这种上调与单个核细胞的间质积累和肌成纤维细胞活性的增加有关，因此表明这些介质是IMN进展的潜在预测因子。最后，根据实验数据和本文的发现，我们推测严重蛋白尿是导致这些因子在小管上皮细胞中上调的主要因素。
Background. Proteinuria plays a central role in the progression of glomerular disease, and there is growing evidence suggesting that it may determine tubular cell activation with release of chemokines and fibrogenic factors, leading to interstitial inflammatory reaction. However, most studies on this subject have been performed in experimental models, and the experience in human kidney biopsies has been scarce. We analyzed the tissue sections of patients with idiopathic membranous nephropathy (IMN), a noninflammatory glomerular disease that may follow a progressive disease with heavy persistent proteinuria, interstitial cell infiltration, and decline of renal function.Methods. Paraffin-embedded biopsy specimens from 25 patients with IMN (13 progressive and 12 nonprogressive) were retrospectively studied by immunohistochemistry [monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted chemokine (RANTES), osteopontin (OPN), platelet-derived growth factor-BE (PD-GF-BB)] and in situ hybridization [MCP-1, RANTES, PDGF-BB, transforming growth factor-beta 1 (TGF-beta 1)]. Moreover, we studied the presence of myofibroblasts, which were identified by the expression of alpha-smooth muscle actin (alpha-SMA), the monocytes/macrophages (CD68-positive cells), and T-cell infiltration (CD4+ and CD8+ cells). All of the patients were nephrotic and without treatment at time of the biopsy.Results. A strong up-regulation of MCP-1, RANTES, and OPN expression was observed, mainly in tubular epithelial cells, with a significant major intensity in the progressive IMN patients. A strong correlation between the mRNA expression and the corresponding protein was noted. The presence of these chemokines and OPN was associated with interstitial cell infiltration. TGF-beta and PDGF were also up-regulated, mainly in tubular epithelial cells, with a stronger expression in the progressive IMN, and an association with the presence of myofibroblasts was found.Conclusions. Patients with severe proteinuria and progressive IMN have an overexpression in tubular epithelial cells of the chemokines MCP-1, RANTES, and OPN and the profibrogenic cytokines PDGF-BB and TGF-beta. Because this upregulation was associated with an interstitial accumulation of mononuclear cells and an increase in myofibroblastic activity, it is suggested that those mediators are potential predictors of progression in IMN. Finally, based on experimental data and the findings of this article, we speculate that severe proteinuria is the main factor responsible for the up-regulation of these factors in tubular epithelial cells.