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

Abstract

Background. In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the α5 chain of type IV collagen result in progressive renal failure. This nephropathy appears to relate to the arrest of a switch from an α1/α2 to an α3/α4/α5 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 COLAA5 mutation. The electron microscopic appearance and the expression of the α1- α6 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 α1-α5 chains. Prior to this stage, only α1 and α2 chains were present, with rare glomeruli positive for the α5 chain. As glomeruli matured, the α1 and α2 chains tended to disappear from the GBM, with the α3-α5 chains remaining. In affected male dogs, only the α1 and α2 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 α3/α4/α5 network and a persistence of the α1/α2 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 α1/α2 network is essential for normal glomerular development, whereas the α3/α4/α5 network is essential for long-term maintenance of glomerular structure and function.