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

Abstract

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.

• Authors: Oliver Gross, Rainer Girgert, Bogdan Beirowski, Matthias Kretzler, Hee Gyung Kang, Jenny Kruegel, Nicolai Miosge, Ann-Christin Busse, Stephan Segerer, Wolfgang F Vogel, Gerhard-Anton Müller, Manfred Weber
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 29 Issue 5 Pg. 346-56 (Jun 2010) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 20307660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier B.V. All rights reserved.

Chemical References

• 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

Topics

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