Transforming growth factor-β1 stimulates collagen matrix remodeling through increased adhesive and contractive potential by human renal fibroblasts

• Published in: Biochimica et biophysica acta. Molecular cell research 2004-08, Vol.1693 (2), p.91-100
• Main Authors: Kondo, Shuji, Kagami, Shoji, Urushihara, Maki, Kitamura, Akiko, Shimizu, Maki, Strutz, Frank, Müller, Gerhard A, Kuroda, Yasuhiro
• Format: Article
• Language: English
• Subjects: Collagen gel contraction; Integrin; Transforming growth factor-β1; α-Smooth muscle actin
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2004.05.005

Renal tubulointerstitial fibrosis is the common final pathway leading to end-stage renal failure. Tubulointerstitial fibrosis is characterized by fibroblast proliferation and excessive matrix accumulation. Transforming growth factor-β1 (TGF-β1) has been implicated in the development of renal fibrosis accompanied by α-smooth muscle actin (α-SMA) expression in renal fibroblasts. To investigate the molecular and cellular mechanisms involved in tubulointerstitial fibrosis, we examined the effect of TGF-β1 on collagen type I (collagen) gel contraction, an in vitro model of scar collagen remodeling. TGF-β1 enhanced collagen gel contraction by human renal fibroblasts in a dose- and time-dependent manner. Function-blocking anti-α1 or anti-α2 integrin subunit antibodies significantly suppressed TGF-β1-stimulated collagen gel contraction. Scanning electron microscopy showed that TGF-β1 enhanced the formation of the collagen fibrils by cell attachment to collagen via α1β1 and α2β1 integrins. Flow cytometry and cell adhesion analyses revealed that the stimulation of renal fibroblasts with TGF-β1 enhanced cell adhesion to collagen via the increased expression of α1 and α2 integrin subunits within collagen gels. Fibroblast migration to collagen was not up-regulated by TGF-β1. Furthermore, TGF-β1 increased the expression of a putative contractile protein, α-SMA, by human renal fibroblasts in collagen gels. These results suggest that TGF-β1 stimulates fibroblast–collagen matrix remodeling by increasing both integrin-mediated cell attachment to collagen and α-SMA expression, thereby contributing to pathological tubulointerstitial collagen matrix reorganization in renal fibrosis.