BACKGROUND - In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen result in progressive renal failure. This nephropathy appears to relate to the arrest of a switch from an alpha 1/alpha 2 to an alpha 3/alpha 4/alpha 5 network of type IV collagen in the developing glomerular basement membrane (GBM; Kalluri et al, J Clin Invest 99:2470, 1997).
METHODS - We examined the role of this switch in glomerular development and function using a canine model of X-linked nephritis with a COL4A5 mutation. The electron microscopic appearance and the expression of the alpha 1-alpha 6 chains of type IV collagen in the GBM was correlated with glomerular function.
RESULTS - In normal neonatal glomeruli, once capillary loops were present, there was staining of GBM for the alpha 1-alpha 5 chains. Prior to this stage, only alpha 1 and alpha 2 chains were present, with rare glomeruli positive for the alpha 5 chain. As glomeruli matured, the alpha 1 and alpha 2 chains tended to disappear from the GBM, with the alpha 3-alpha 5 chains remaining. In affected male dogs, only the alpha 1 and alpha 2 chains were detected at any stage. GBM ultrastructure in these dogs remained normal until one month and proteinuria did not appear until two months.
CONCLUSION - Our results show that normal glomerular development involves a switch in type IV collagen networks. In affected male dogs, a failure of this switch results in an absence of the alpha 3/alpha 4/alpha 5 network and a persistence of the alpha 1/alpha 2 network in GBM. GBM ultrastructure and glomerular function remain normal for one month, indicating that GBM deterioration in Alport syndrome begins as a postnatal process. Hence, only the alpha 1/alpha 2 network is essential for normal glomerular development, whereas the alpha 3/alpha 4/alpha 5 network is essential for long-term maintenance of glomerular structure and function.