TUBULAR EPITHELIAL-MYOFIBROBLAST TRANSDIFFERENTIATION IN PROGRESSIVE TUBULOINTERSTITIAL FIBROSIS IN 5 6-NEPHRECTOMIZED RATS/

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 w eeks 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 asso ciated with disruption of the tubular basement membrane (TBM). This ph enotypic evidence of tubular epithelial-myofibroblast transdifferentia tion was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC wi th a transformed morphology. In the late stage of this apparent tubula r 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 pe ritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of alpha-SMA(+) myofibroblasts and loca l tubulointerstitial fibrosis was closely associated with alpha-SMA(+) tubules, suggesting a tubular epithelial origin for some of these cel ls. 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 morp hological evidence to support the hypothesis that TEC are pro-fibrogen itor cells capable of tubular epithelial-myofibroblast transdifferenti ation in progressive renal fibrosis. In addition, we postulate that di sruption of the TBM, which facilitates epithelial cell contact with th e interstitial matrix, promotes this process of transdifferentiation.