Loss of α3/α4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to α5α6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice

Mutations in COL4A3/4/5 genes that affect the normal assembly of the alpha 3/4/5(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. Col4a(-/-) 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 Col4 alpha 3(-/-) Alport mice. The downregulation or the absence of alpha 3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col40(-/-) mice was found to induce ectopic deposition of alpha 5/6(IV) collagen. The GBM deposition of a5/6(IV) collagen was abundant in C57BL/6 Col40(-/-) mice but almost undetectable in 129X1/Sv Col40(-/-) mice. This strain difference was due to overall low expression of alpha w(IV) chain and alpha 5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 X B6)F1 Col4a3(-/-) mice, the amount of alpha 5/6(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 a5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that a5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for a3/4/5(IV) collagen. Therapeutically induced GBM deposition of a5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.