Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes
proteinuria and renal
fibrosis in the
type IV collagen disease
Alport syndrome. This study evaluates the role of
collagen receptors in maturation of the GBM, matrix accumulation and renal
fibrosis by using mice deficient for
discoidin domain receptor 1 (DDR1),
integrin subunit α2 (ITGA2), and
type IV collagen α3 (COL4A3). Loss of both
collagen receptors DDR1 and
integrin α2β1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight
proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes
proteinuria to drop down to one tenth until day 200.
Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as
Alport syndrome, loss of
integrin α2β1 positively delays renal
fibrosis: COL4A3(-/-)/ITGA2(-/-) double knockouts exhibited reduced
proteinuria and
urea nitrogen compared to COL4A3(-/-)/ITGA2(+/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal
integrin α2β1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the
collagen receptors DDR1 and
integrin α2β1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the
type IV collagen disease
Alport syndrome, glomerular cell-matrix interactions via
collagen receptors play an important role in the progression of renal
fibrosis.