Received February 22, 2006
Accepted on April 15, 2006

BASIC SCIENCE: Pathophysiology of Renal Disease and Progression

Loss of 3/4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to 56(IV) Collagen Associated with Longer Renal Survival in Col4a3^-/- Alport Mice

Jeong Suk Kang ^*, Xu-Ping Wang ^*, Jeffrey H. Miner , Roy Morello , Yoshikazu Sado , Dale R. Abrahamson ^||, and Dorin-Bogdan Borza ^*1

*Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Renal Division, Washington University School of Medicine, St. Louis, Missouri; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Shigei Medical Research Institute, Okayama, Japan; and ||Department of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City, Kansas

¹ To whom correspondence should be addressed. E-mail: Dorin-Bogdan.Borza{at}vanderbilt.edu.

	Abstract

Mutations in COL4A3/4/5 genes that affect the normal assembly of the 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. 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 3/4(IV) collagen chains in the GBM of Lmx1b-/- and Col4a3-/- mice was found to induce ectopic deposition of 5/6(IV) collagen. The GBM deposition of 5/6(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 6(IV) chain and 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 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 5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that 5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for 3/4/5(IV) collagen. Therapeutically induced GBM deposition of 5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.