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.
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.
Authors: Oliver Gross; Dorin-Bogdan Borza; Hans-Joachim Anders; Christoph Licht; Manfred Weber; Stephan Segerer; Roser Torra; Marie-Claire Gubler; Laurence Heidet; Scott Harvey; Dominic Cosgrove; George Lees; Clifford Kashtan; Martin Gregory; Judy Savige; Jie Ding; Paul Thorner; Dale R Abrahamson; Corinne Antignac; Karl Tryggvason; Billy Hudson; Jeffrey H Miner Journal: Nephrol Dial Transplant Date: 2008-12-25 Impact factor: 5.992
Authors: Scott J Harvey; Julie Perry; Keqin Zheng; Dilys Chen; Yoshikazu Sado; Barbara Jefferson; Yoshifumi Ninomiya; Robert Jacobs; Billy G Hudson; Paul S Thorner Journal: Am J Pathol Date: 2006-05 Impact factor: 4.307