Ng Y Y, Huang T P, Yang W C, Chen Z P, Yang A H, Mu W, Nikolic-Paterson D J, Atkins R C, Lan H Y
Department of Nephrology, Veterans General Hospital-Taipei, National Yang-Ming University, Taiwan.
Kidney Int. 1998 Sep;54(3):864-76. doi: 10.1046/j.1523-1755.1998.00076.x.
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.
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.
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).
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.
肾小管间质纤维化是终末期肾衰竭的最终共同途径。本研究在大鼠残余肾模型中探讨了肾小管上皮细胞（TEC）在进行性纤维化中的潜在作用。
大鼠接受5/6肾切除术或假手术（对照），每组6只动物在第1、3、5、9、13、17和21周处死。
肾切除术后第3周的免疫组织化学染色和原位杂交显示，TEC从头表达α-平滑肌肌动蛋白（α-SMA）——平滑肌细胞和成肌纤维细胞的标志物——这始终与肾小管基底膜（TBM）的破坏有关。超微结构研究证实TEC内存在特征性肌动蛋白微丝和致密体，形态发生改变，支持了这种肾小管上皮-成肌纤维细胞转分化的表型证据。在这种明显的肾小管上皮-成肌纤维细胞转分化的后期，TEC失去顶-基极性和紧密连接，变得细长，与TBM分离，与相邻细胞分开，并似乎通过受损的基底膜迁移到肾小管周围间质。实际上，α-SMA+成肌纤维细胞在肾小管周围的局灶性积聚和局部肾小管间质纤维化与α-SMA+小管密切相关，提示其中一些细胞起源于肾小管上皮。定量分析发现，α-SMA+ TEC的数量与间质α-SMA+成肌纤维细胞的积聚以及肾小管间质纤维化的严重程度之间存在显著相关性（均P < 0.001）。
本研究提供了表型和形态学证据，支持TEC是进行性肾纤维化中能够发生肾小管上皮-成肌纤维细胞转分化的促纤维化祖细胞这一假说。此外，我们推测TBM的破坏促进了上皮细胞与间质基质的接触，从而推动了这种转分化过程。
