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

详细信息    查看全文

• 作者：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 Mü ; ller ; Man
• 关键词：Type IV collagen ; Collagen receptors ; Alport syndrome ; Renal fibrosis ; Hereditary kidney disease
• 刊名：Matrix Biology
• 出版年：2010
• 出版时间：June 2010
• 年：2010
• 卷：29
• 期：5
• 页码：346-356
• 全文大小：2560 K

文摘

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 6 years. 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 proinflammtory, profibrotic cells via signaling of TGFβ, CTGF, NFκB 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.