Localisation and phenotypical characterisation of collagen-producing cells in TGF-β1-induced renal interstitial fibrosis

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Abstract
Transforming growth factor β1 (TGF-β1) contributes to the accumulation of extracellular matrix (ECM) in the tubulointerstitial space in chronic renal diseases. Identification of target cells and the contribution of epithelial–mesenchymal transformation (EMT) in TGF-β1-induced fibrosis in vivo are currently under investigation. We have developed a transgenic model of slowly developing TGF-β1-driven tubulointerstitial fibrosis (TIF). By using this model our aim was to localise the ECM-producing cells, to investigate the temporal and spatial distribution of the cellular markers α-smooth muscle cell actin (αSM-actin), Fsp1 and Hsp47 and to explore the possible involvement of EMT in TGF-β1-induced TIF in vivo. We utilised a combination of in situ hybridisation, immunohistochemistry and western blotting techniques and found that αSM-actin-positive interstitial cells are the main source of collagen types I and III and fibronectin, whereas collagen type IV(α1/α2) originates mainly from the tubular epithelial cells. Furthermore, macrophages are not important combatants during the early course of TGF-β1-induced TIF. Finally, EMT is not necessary for the initiation of TGF-β1-induced TIF. We conclude, that intervention directed against the recruitment of activated interstitial cells may avoid the development of end-stage renal disease.