Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation.
Type IV collagen is a major component of basement membranes and it provides structural and functional support to various cell types. Type IV collagen exists in a highly complex suprastructure form and recent studies implicate that protomer (the trimeric building unit of type IV collagen) assembly is mediated by the NC1 domain present in the C-terminus of each collagen alpha-chain polypeptide. Here we show that type IV collagen contributes to the maintenance of the epithelial phenotype of proximal tubular epithelial cells, whereas type I collagen promotes epithelial-to-mesenchymal transdifferentiation (EMT). In addition, the recombinant human alpha1NC1 domain inhibits assembly of type IV collagen NC1 hexamers and potentially disrupts the deposition of type IV collagen, facilitating EMT in vitro. Inhibition of type IV collagen assembly by the alpha1NC1 domain up-regulates the production of transforming growth factor-beta1 in proximal tubular epithelial cells, an inducer of EMT. These results strongly suggest that basement membrane architecture is pivotal for the maintenance of epithelial phenotype and that changes in basement membrane architecture potentially lead to up-regulation of transforming growth factor-beta1, which contributes to EMT during renal fibrosis.
Zeisberg
M
M
Program in Matrix Biology, Department of Medicine and the Liver Center, Renal Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Bonner
G
G
Maeshima
Y
Y
Colorado
P
P
Müller
G A
GA
Strutz
F
F
Kalluri
R
R
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D017434:Protein Structure, Tertiary / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
D024141:Collagen Type IV; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1