Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis

There is much debate over the origins of fibroblast-type cells that accumul ate in interstitial fibrosis. A controversial hypothesis, supported by data from animal and cell-culture studies, is that fibroblast-type cells can de rive from tubular epithelial cells by a process of epithelial-mesenchymal t ransdifferentiation. However, to date, no evidence supports this postulate in human glomerulonephritis. This study sought to provide evidence that tub ular epithelial cells can undergo phenotypic change toward a fibroblast-lik e cell in human glomerulonephritis. One hundred twenty-seven open renal bio psy specimens from patients with minimal change disease (MCD), immunoglobul in A (IgA) nephropathy, and rapidly progressive glomerulonephritis (RPGN) w ere examined for tubular phenotypic change by two-color immunohistochemistr y using the criteria of de novo expression of a-smooth muscle actin (alpha -SMA), a myofibroblast marker; loss of the epithelial marker cytokeratin; a nd collagen production. In normal human kidney and MCD, tubular epithelial cells expressed cytokeratin with no evidence of alpha -SMA staining. Howeve r, in 36 of 90 cases of IgA nephropathy and 9 of 18 cases of RPGN, small nu mbers of tubular epithelial cells in areas of fibrosis showed de novo a-SMA expression, accounting for 0.4% +/- 0.2% (IgA nephropathy) and 3.8% +/- 1. 5% (RPGN) of cortical tubules. An intermediate stage of phenotypic change w as observed in some cuboidal epithelial cells that expressed both cytokerat in and alpha -SMA. Tubules containing alpha -SMA-positive (alpha -SMA(+)) c ells also stained for collagen types I and III, suggesting that tubular cel ls undergoing phenotypic change have an active role in the fibrotic process . There also was a marked increase in transforming growth factor-beta1 (TGF -beta1) tubular expression in areas with interstitial fibrosis, including t ubules with phenotypic change. There was a highly significant correlation b etween tubular a-SMA expression and interstitial fibrosis, interstitial a-S MA+ myofibroblast accumulation, deposition of collagen types I and III, tub ular TGF-beta1 expression, and renal dysfunction. In conclusion, this study provides evidence that tubular epithelial cells can undergo phenotypic cha nge toward a myofibroblast-like phenotype on the basis of de novo a-SMA exp ression, loss of cytokeratin, and de novo collagen staining. These data, al though not conclusive, provide the first support for the hypothesis that tr ansdifferentiation of tubular epithelial cells has a role in progressive re nal fibrosis in human glomerulonephritis. (C) 2001 by the National Kidney F oundation, Inc.