Role of distinct type IV collagen networks in glomerular development and function

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 ct 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 GEM was correlated with glomerular function. Results. In normal neonatal glomeruli, once capillary loops were present, there was staining of GEM 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 GEM, 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. GEM 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 GEM. GEM ultrastructure and glomerular function remain normal for one month, indicating that GEM 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.