Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats
Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats
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DOI：
10.1046/j.1523-1755.1998.00076.x
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发表时间：
1998-09-01
影响因子：
19.6
通讯作者：
Lan, HY
中科院分区：
文献类型：
--
作者：
Ng, YY;Huang, TP;Lan, HY
背景肾小管间质纤维化是终末期肾衰竭的最终共同途径。本研究探讨肾小管上皮细胞（TEC）在大鼠残肾纤维化中的作用。分别于第1、3、5、9、13、17、21周处死大鼠，每组6只。免疫组织化学染色和原位杂交显示，在肾切除术后3周的新生表达α-平滑肌肌动蛋白（α-SMA）-平滑肌细胞和肌纤维母细胞的标志物，TEC总是与破坏的肾小管基底膜（TBM）。这种表型证据的肾小管上皮细胞-肌成纤维细胞转分化的超微结构研究，确定存在的特征性肌动蛋白微丝和致密体内TEC与转化形态的支持。在这种明显的肾小管上皮细胞-肌成纤维细胞转分化的晚期阶段，TEC失去了顶部-基底极性和紧密连接，变得细长，从TBM上脱离，与邻近细胞分离，并似乎通过受损的基底膜迁移到肾小管周上皮细胞中。事实上，α-SMA（+）肌成纤维细胞的局灶性肾小管周围蓄积和局部肾小管间质纤维化与α-SMA（+）小管密切相关，表明其中一些细胞起源于肾小管上皮。定量分析发现，α-SMA（+）TEC的数量和间质中α-SMA（+）肌成纤维细胞的积聚与肾小管间质纤维化的严重程度显著相关（均P <0. 001）。本研究提供了表型和形态学证据来支持这一假设，即TEC是促纤维生成细胞，能够在进行性肾纤维化中进行肾小管上皮-肌成纤维细胞转分化。此外，我们假设，破坏的TBM，这有利于上皮细胞与间质基质的接触，促进这一过程的转分化。
Background. Tubulointerstitial fibrosis is the final common pathway to end-stage renal failure. The present study investigated the potential role of tubular epithelial cells (TEC) in progressive fibrosis in the rat remnant kidney model.Methods. Rats underwent 5/6 nephrectomy or a sham operation (control), and groups of six animals were killed at weeks 1, 3, 5, 9, 13, 17 and 21.Results. Immunohistochemistry staining and in situ hybridization at week 3 after nephrectomy demonstrated de novo expression of alpha-smooth muscle actin (alpha-SMA)-a marker of smooth muscle cells and myofibroblasts-by TEC that was invariably associated with disruption of the tubular basement membrane (TBM). This phenotypic evidence of tubular epithelial-myofibroblast transdifferentiation was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC with a transformed morphology. In the late stage of this apparent tubular epithelial-myofibroblast transdifferentiation, TEC lost apical-basal polarity and tight junctions, became elongated, detached from the TBM, separated from neighboring cells and appeared to migrate into the peritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of alpha-SMA(+) myofibroblasts and local tubulointerstitial fibrosis was closely associated with alpha-SMA(+) tubules, suggesting a tubular epithelial origin for some of these cells. Quantitative analysis found a significant correlation between the number of alpha-SMA(+) TEC and the accumulation of interstitial alpha-SMA(+) myofibroblasts and the severity of tubulointerstitial fibrosis (both P < 0.001).Conclusions. This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of transdifferentiation.