Siddiqui Iram, Khan Zia A, Lian Dameng, Jiang Jifu, Zhong Robert, Garcia Bertha, Chakrabarti Subrata
Department of Pathology, University of Western Ontario, London, Canada.
Transplantation. 2006 Aug 15;82(3):406-14. doi: 10.1097/01.tp.0000228905.44649.06.
Chronic allograft nephropathy is a sclerotic process characterized by an increased extracellular matrix (ECM) protein deposition. Fibronectin (FN) is a major component of ECM. FN has been reported to undergo alternative splicing and produce several isoforms including the extra domain-B (ED-B) containing embryonic isoform. In the present study, we investigated ED-B FN expression in chronic allograft nephropathy and its relationship with endothelins (ET).
To establish chronic allograft nephropathy, allografts were performed between Fisher 344 --> Lewis rats. Allograft recipients were then randomly divided into two groups, allografts and allografts treated with ET receptor antagonist bosentan. Lewis --> Lewis recipients were used as isograft controls. Grafts were harvested at 30, 90 and 140 days for histological and gene expression analyses with respect to ED-B FN, ET-1 and transforming growth factor-beta1 (TGF-beta1) mRNA. ED-B FN protein levels were assessed by immunohistochemical analysis. Additionally, we analyzed human renal allograft biopsies.
Our data demonstrates that rat chronic allograft nephropathy is associated with progressive upregulation of ED-B FN mRNA and protein. ET-1 and TGF-beta1 mRNA were also upregulated. Treatment of allograft recipient rats with bosentan prevented upregulation of ED-B FN and TGF-beta1. We further show that total FN, ED-B FN, ET-1 and TGF-beta1 mRNA expression were upregulated in human chronic allograft nephropathy specimens.
Results obtained from both human and rat renal allograft tissues suggest that expression of ED-B FN is upregulated in chronic allograft nephropathy and such upregulation is mediated via ET-1 and its interaction with TGF-beta1.
慢性移植肾肾病是一种以细胞外基质（ECM）蛋白沉积增加为特征的硬化过程。纤连蛋白（FN）是ECM的主要成分。据报道，FN会发生可变剪接并产生几种异构体，包括含有额外结构域B（ED-B）的胚胎异构体。在本研究中，我们调查了慢性移植肾肾病中ED-B FN的表达及其与内皮素（ET）的关系。
为建立慢性移植肾肾病模型，在Fisher 344大鼠与Lewis大鼠之间进行同种异体移植。然后将同种异体移植受体随机分为两组，即同种异体移植组和用ET受体拮抗剂波生坦治疗的同种异体移植组。Lewis大鼠之间的移植受体用作同基因移植对照。在第30、90和140天采集移植物，进行关于ED-B FN、ET-1和转化生长因子-β1（TGF-β1）mRNA的组织学和基因表达分析。通过免疫组织化学分析评估ED-B FN蛋白水平。此外，我们分析了人类肾移植活检标本。
我们的数据表明，大鼠慢性移植肾肾病与ED-B FN mRNA和蛋白的逐渐上调有关。ET-1和TGF-β1 mRNA也上调。用波生坦治疗同种异体移植受体大鼠可防止ED-B FN和TGF-β1的上调。我们进一步表明，在人类慢性移植肾肾病标本中，总FN、ED-B FN、ET-1和TGF-β1 mRNA表达上调。
从人类和大鼠肾移植组织获得的结果表明，慢性移植肾肾病中ED-B FN的表达上调，且这种上调是通过ET-1及其与TGF-β1的相互作用介导的。
