The IV chains of mature GBM
The α3/α4/α5(IV)-chains of mature GBM are built exclusively by podocytes (not by endothelial cells) (Abrahamson et al., 2009), placing the podocytes into the focus of GBM-diseases such as Alport syndrome. Alport syndrome (AS) is caused by mutations in the COL4A3, 4 or 5 genes coding for the α3/α4/α5-chains of type IV collagen. AS is characterized by hematuria and proteinuria, progressive renal failure, sensorineural deafness, and typical ocular changes (Hudson et al., 2003, Kashtan, 2004). AS affects about 1:10,000 children and usually leads to end stage renal failure during adolescence. While the loss of the α3/α4/α5-chains in AS leads to characteristic ultra-structural changes within the GBM, the chain of molecular events leading from mutation in a type IV collagen gene to progressive renal scarring and loss of kidney function has yet to be determined. αβ integrin plays a distinct role in pathogenesis of AS (Cosgrove et al., 2000). The role of further collagen receptors (other than integrins) such as DDR1 has not been addressed previously.
DDR1 and DDR2 are receptor tyrosine kinases with a characteristic extracellular discoidin element (Vogel et al., 2000). DDR1 is activated by triple-helical collagens such as type I and IV independently from integrins (Vogel et al., 2000). In adherent cells, highest DDR1 phosphorylation is reached after several hours of collagen stimulation (L\'hote et al., 2002). DDR1 mRNA expression is predominantly seen in epithelial cells, particularly within the kidney, lung, gastrointestinal tract, and brain; however, little is known about its precise cellular distribution (Vogel et al., 2006).
Deletion of DDR1 in the mouse germ line resulted in viable animals with hearing loss (Meyer zum Gottesberge et al., 2007), females show defect blastocyst-implantation and mammary gland development (Vogel et al., 2006). Vascular smooth muscle hepititis b from DDR1-null mice show decreased proliferation, collagen-attachment, and migration, pointing to a role of DDR1 in atherosclerosis (Franco et al., 2008). DDR1 controls growth and adhesion of renal mesangial cells (Curat and Vogel, 2002). Further, deletion of DDR1 protects – to a certain extent – from hypertension-induced renal disease (Flamant et al., 2006) as well as from bleomycin-induced pulmonary fibrosis by influencing leukocyte differentiation, collagen production, myofibroblast expansion, apoptosis and NFκB-activation (Avivi-Green et al., 2006). DDR1−/− mice develop mild proteinuria due to altered GBM morphology, but no progressive renal disease or loss of renal function (Gross et al., 2004b).
These data indicate a possible general role of DDR1 in chronic inflammatory and fibrotic renal diseases (Ronco and Chatziantoniou, 2008), which is investigated in the present study. Additionally, previous data in COL4A3−/− mice pointed to a possible role of DDR1 in Alport disease (Gross et al., 2004a). The present study demonstrates that DDR1 is expressed in glomerular epithelial cells (podocytes). Loss of DDR1 in Alport-mice delays renal fibrosis and inflammation. Podocyte–matrix interaction via DDR1 plays a role in AS and might have a universal role in common human inflammatory and fibrotic diseases. Therefore, the blockade of DDR1 might become an important new therapeutic concept in progressive fibrosis and inflammation in the future.
Discussion DDR−/− mice develop a mild renal phenotype without renal failure and without severe proteinuria (Gross et al. 2004b). Their local defect of the GBM affected less than 2% of the total GBM-area only. Further, their mild renal phenotype showed up later in life (6 to 9months of age) compared to the two to three month old Double-knockout mice used in the present study. Our findings on the collagen-receptor DDR1 are in accordance to a previous study by Cosgrove and coworkers about the collagen-receptor α1/β1 integrin (Cosgrove et al., 2000). The present study further reinforces the role of the collagen-receptor DDR1 in chronic renal fibrosis by improving the hard end point lifespan until death from renal failure. Additionally, the localization of the collagen-receptor DDR1 at the lateral base of podocytes points to an important role of DDR1 in matrix–cell interaction between GBM and podocyte. Activation of DDR1 requires a transmembrane leucine zipper (Noordeen et al., 2006) and four neighboring, surface-exposed collagen-loops (Abdulhussein et al., 2008). These collagen-loops can be altered by glycine mutations in AS. AS patients with a 3′ glycine mutation develop a different phenotype than patients with 5′ glycine mutations (Gross et al., 2002). Different mutated collagen-loops might result in different binding affinity to collagen receptors such as DDR1. Therefore, DDR1 seems to play an important role in pathogenesis of AS.