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 α3/4/5(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 Ι3/4(IV) collagen chains in the GBM of Lmx1b^-/- and Col4a3^-/- mice was found to induce ectopic deposition of α5/6(IV) collagen. The GBM deposition of α5/6(IV) collagen was abundant in C57BL/6 Col4a3^-/- mice but almost undetectable in 129X1/SvJ Col4a3^-/- mice. This strain difference was due to overall low expression of α6(IV) chain and α5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 × B6)F1 Col4a3^-/- mice, the amount of α5/6(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 α5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that α5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for α3/4/5(IV) collagen. Therapeutically induced GBM deposition of α5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.