Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease

Matrix Biol. 2010 Jun;29(5):346-56. doi: 10.1016/j.matbio.2010.03.002. Epub 2010 Mar 20.


Alport syndrome is a hereditary type IV collagen disease leading to progressive renal fibrosis, hearing loss and ocular changes. End stage renal failure usually develops during adolescence. COL4A3-/- mice serve as an animal model for progressive renal scarring in Alport syndrome. The present study evaluates the role of Discoidin Domain Receptor 1 (DDR1) in cell-matrix interaction involved in pathogenesis of Alport syndrome including renal inflammation and fibrosis. DDR1/COL4A3 Double-knockouts were compared to COL4A3-/- mice with 50% or 100% expression of DDR1, wildtype controls and to DDR1-/- COL4A3+/+ controls for over 6years. Double-knockouts lived 47% longer, mice with 50% DDR1 lived 29% longer and showed improved renal function (reduction in proteinuria and blood urea nitrogen) compared to animals with 100% DDR1 expression. Loss of DDR1 reduced proinflammatory, profibrotic cells via signaling of TGFbeta, CTGF, NFkappaB and IL-6 and decreased deposition of extracellular matrix. Immunogold-staining and in-situ hybridisation identified podocytes as major players in DDR1-mediated fibrosis and inflammation within the kidney. In summary, glomerular epithelial cells (podocytes) express DDR1. Loss of DDR1-expression in the kidney delayed renal fibrosis and inflammation in hereditary type IV collagen disease. This supports our hypothesis that podocyte-matrix interaction via collagen receptors plays an important part in progression of renal fibrosis in Alport disease. The blockade of collagen-receptor DDR1 might serve as an important new therapeutic concept in progressive fibrotic and inflammatory diseases in the future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism*
  • Connective Tissue Growth Factor / metabolism
  • Discoidin Domain Receptor 1
  • Female
  • Fibrosis / metabolism
  • Fibrosis / physiopathology*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / physiopathology*
  • Kidney Glomerulus / ultrastructure
  • Longevity
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • Microscopy, Electron
  • NF-kappa B / metabolism
  • Nephritis, Hereditary / metabolism
  • Nephritis, Hereditary / physiopathology*
  • Proteinuria / metabolism
  • RNA / chemistry
  • RNA / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / metabolism
  • Urea / blood


  • CCN2 protein, mouse
  • CD3 Complex
  • Collagen Type IV
  • NF-kappa B
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • RNA
  • Urea
  • Ddr1 protein, mouse
  • Discoidin Domain Receptor 1
  • Receptor Protein-Tyrosine Kinases