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(American Journal of Pathology. 2001;159:1313-1321.)
© 2001 American Society for Investigative Pathology

Regular Articles

Renal Fibrosis

Collagen Composition and Assembly Regulates Epithelial-Mesenchymal Transdifferentiation

Michael Zeisberg*, Gary Bonner*, Yohei Maeshima*, Pablo Colorado*, Gerhard A. Müller{dagger}, Frank Strutz{dagger} and Raghu Kalluri*

From the Program in Matrix Biology,*
Department of Medicine and the Liver Center, Renal and Gastroenterology Divisions, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and the Department of Nephrology and Rheumatology,{dagger}
Georg-August University Medical Center, Göttingen, Germany

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 {alpha}1NC1 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 {alpha}1NC1 domain up-regulates the production of transforming growth factor-ß1 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-ß1, which contributes to EMT during renal fibrosis.




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