The membrane attack complex, C5b-9, up regulates collagen gene expression in renal tubular epithelial cells
The membrane attack complex, C5b-9, up regulates collagen gene expression in renal tubular epithelial cells
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DOI：
10.1111/j.1365-2249.2004.02411.x
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发表时间：
2004-04-01
影响因子：
4.6
通讯作者：
Sheerin, NS
中科院分区：
文献类型：
--
作者：
Abe, K;Li, K;Sheerin, NS
越来越多的证据表明蛋白尿在肾小管间质纤维化的发病机制中起直接作用。然而，蛋白尿导致损伤的机制尚不清楚。在蛋白尿状态下，补体蛋白通过肾小球过滤，并可能导致肾小管损伤。本研究的目的是探讨补体激活在间质纤维化进展中的作用。为了确定补体激活是否可能是导致肾小管间质区室中发生的促纤维化反应的原因，我们用膜攻击复合物C5 b-9刺激近端肾小管上皮细胞的原代培养物。这导致IV型胶原及其细胞内伴侣热休克蛋白47（HSP 47）的mRNA浓度增加。为了确定这是否在体内发生，使用阿霉素在雌性Balb/c小鼠中诱导蛋白尿。与对照组小鼠相比，蛋白尿小鼠中IV型胶原和HSP 47的表达增加。在蛋白尿小鼠肾脏中，C3沉积在肾小管间质损伤的部位，并且C3沉积与IV型胶原和HSP 47的免疫化学染色之间存在关系。原位杂交结果表明，肾小管上皮细胞积极表达HSP 47 mRNA，并暗示，过量的胶原。这些观察结果支持以下假设：肾小管上皮细胞上的补体激活可直接增加与肾小管间质损伤相关的促纤维化过程。
Evidence suggesting a direct role for proteinuria in the pathogenesis of renal tubulointerstitial fibrosis is accumulating. However the mechanism by which proteinuria leads to injury is unknown. In proteinuric states complement proteins are filtered through the glomerulus and could contribute to the tubular damage. The aim of this study was to investigate the role of complement activation in the progression of interstitial fibrosis. To determine whether complement activation may be responsible for the pro-fibrotic response that occurs in the tubulointerstitial compartment we stimulated primary cultures of proximal tubular epithelial cells with membrane attack complex, C5b-9. This led to increased mRNA concentrations of both collagen type IV and its intracellular chaperone, Heat Shock Protein 47 (HSP47). To determine whether this occurred in vivo Adriamycin was used to induce proteinuria in female Balb/c mice. The expression of collagen type IV and HSP47 was increased in proteinuric mice compared to control mice. In proteinuric mouse kidney, C3 was deposited at sites of tubulointerstitial injury and there was a relationship between C3 deposition and immunochemical staining for collagen type IV and HSP47. In situ hybridization suggested that the renal tubular epithelium was actively expressing HSP47 mRNA and, by implication, excess collagen. These observations support the hypothesis that complement activation on tubular epithelial cells can directly increase the pro-fibrotic process associated with tubulointerstitial damage.