Epithelial to mesenchymal transition during late deterioration of human kidney transplants: the role of tubular cells in fibrogenesis.
The hallmark of failing renal transplants is tubular atrophy and interstitial fibrosis (TA/IF). Injury to tubular epithelial cells (TEC) could contribute to fibrogenesis via epithelial-mesenchymal transition (EMT). We examined the features of EMT in renal transplants that developed TA/IF. Biopsies from 10 allograft kidneys with impaired function and TA/IF and 10 biopsies from transplants with stable function were compared to their implantation biopsies. Relative to implantation biopsies, TEC in TA/IF kidneys showed loss of epithelial markers (E-cadherin, cytokeratin) with altered distribution. Some TEC also showed new cytoplasmic expression of mesenchymal markers vimentin, S100A4, and alpha smooth muscle actin (alpha-SMA) and collagen synthesis marker heat shock protein (HSP-47), both in deteriorating and atrophic tubules. Double immunostaining showed coexpression of cytokeratin and vimentin, S100A4 and HSP-47, indicating intermediate stages of EMT in TA/IF. These changes were absent or much less in transplants with stable function. EMT features in the TA/IF group correlated with serum creatinine (vimentin, S100A4, HSP-47), history of T-cell-mediated rejection (cytokeratin, S100A4) and proteinuria (cytokeratin). These findings support a model in which the TEC damage induces loss of epithelial features and expression of fibroblast features, as a common pathway of deterioration by either immunologic or nonimmunologic processes.
Vongwiwatana
Attapong
A
Medicine, Division of Nephrology and Transplantation Immunology, University of Alberta, Edmonton, Canada.
Tasanarong
Adis
A
Rayner
David C
DC
Melk
Anette
A
Halloran
Philip F
PF
D000199:Actins / Q000378:metabolism; D000328:Adult; D001284:Atrophy; D015415:Biomarkers; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D005355:Fibrosis; D006084:Graft Rejection / Q000473:pathology*; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D016030:Kidney Transplantation / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D015843:Serpins / Q000378:metabolism; D014184:Transplantation, Homologous; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D015415:Biomarkers; D015820:Cadherins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C494660:SERPINH1 protein, human; D015843:Serpins; D014746:Vimentin; D007633:Keratins