Chai Qing, Krag Søren, Miner Jeffrey H, Nyengaard Jens Randel, Chai Song, Wogensen Lise
Research Laboratory for Biochemical Pathology, Institute for Experimental Clinical Research, Aarhus Kommunehospital, Aarhus, Denmark.
Nephron Exp Nephrol. 2003;94(4):e123-36. doi: 10.1159/000072496.
Transforming growth factor-beta1 (TGF-beta1) contributes to the thickening of the glomerular basement membrane (GBM), abnormal deposition of extracellular matrix (ECM) therein and expansion of the mesangial matrix (MM) in several glomerular kidney diseases. However, the influence of TGF-beta1 on the expression of collagen IV isotypes and laminin chains in the GBM and the MM in vivo is not known in detail. By using transgenic mice with TGF-beta1 expression targeted to the juxtaglomerular apparatus and a combination of immunohistochemistry, Western blotting, immunoelectron microscopy and in situ hybridization, we investigated the contribution of different laminin chains and collagen type IV isotypes to the basement membrane thickening and mesangial expansion. We report that exposure of the glomerulus to TGF-beta1 in vivo induces aberrant deposition of fetal laminin alpha1, alpha2 and beta1 chains and collagen type IValpha1/alpha2 in the GBM. On the other hand, the TGF-beta1-mediated expansion of the mesangial ECM is dominated by the normal components. We found that the cellular origin of at least laminin alpha1 and alpha2 chains may be the glomerular endothelial cells. We speculate that the endothelial cells could contribute to TGF-beta1-induced glomerulopathy and should be considered as target cells for early intervention in glomerular diseases associated with TGF-beta1 in man.
转化生长因子-β1（TGF-β1）在多种肾小球疾病中导致肾小球基底膜（GBM）增厚、细胞外基质（ECM）在其中异常沉积以及系膜基质（MM）扩张。然而，TGF-β1对体内GBM和MM中IV型胶原异构体及层粘连蛋白链表达的影响尚不清楚。通过使用将TGF-β1表达靶向肾小球旁器的转基因小鼠，并结合免疫组织化学、蛋白质印迹、免疫电子显微镜和原位杂交技术，我们研究了不同层粘连蛋白链和IV型胶原异构体对基底膜增厚和系膜扩张的作用。我们报告称，体内肾小球暴露于TGF-β1会诱导胎儿层粘连蛋白α1、α2和β1链以及IV型胶原α1/α2在GBM中异常沉积。另一方面，TGF-β1介导的系膜ECM扩张主要由正常成分主导。我们发现至少层粘连蛋白α1和α2链的细胞来源可能是肾小球内皮细胞。我们推测内皮细胞可能促成TGF-β1诱导的肾小球病，应被视为人类中与TGF-β1相关的肾小球疾病早期干预的靶细胞。
