Loss of alpha3/alpha4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to alpha5alpha6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice.
Mutations in COL4A3/4/5 genes that affect the normal assembly of the alpha3/4/5(IV) collagen network in the glomerular basement membrane (GBM) cause Alport syndrome. Patients progress to renal failure at variable rates that are determined by the underlying mutation and putative modifier genes. Col4a3(-/-) mice, a model for autosomal recessive Alport syndrome, progress to renal failure significantly slower on the C57BL/6 than on the 129X1/Sv background. Reported here is a novel strain-specific alternative collagen IV isoform switch that is associated with the differential renal survival in Col4a3(-/-) Alport mice. The downregulation or the absence of alpha3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col4a3(-/-) mice was found to induce ectopic deposition of alpha5/6(IV) collagen. The GBM deposition of alpha5/6(IV) collagen was abundant in C57BL/6 Col4a3(-/-) mice but almost undetectable in 129X1/Sv Col4a3(-/-) mice. This strain difference was due to overall low expression of alpha6(IV) chain and alpha5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 x B6)F1 Col4a3(-/-) mice, the amount of alpha5/6(IV) collagen in the GBM was inherited in a mother-to-son manner, suggesting that it is controlled by one or more X-linked loci, possibly Col4a6 itself. Importantly, high levels of ectopic alpha5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that alpha5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for alpha3/4/5(IV) collagen. Therapeutically induced GBM deposition of alpha5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.
Kang
Jeong Suk
JS
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2372, USA.
Wang
Xu-Ping
XP
Miner
Jeffrey H
JH
Morello
Roy
R
Sado
Yoshikazu
Y
Abrahamson
Dale R
DR
Borza
Dorin-Bogdan
DB
D000818:Animals; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D009394:Nephritis, Hereditary / Q000235:genetics*; D020033:Protein Isoforms; D013534:Survival; D014960:X Chromosome / Q000235:genetics
D024141:Collagen Type IV; D020033:Protein Isoforms