Endothelial Cell-specific Collagen Type IV-α Expression Does Not Rescue Alport Syndrome in Col4a3 Mice

The glomerular basement membrane (GBM) is a critical component of the kidney's blood filtration barrier. Alport syndrome, a hereditary disease leading to kidney failure, is caused by the loss or dysfunction of the GBM's major collagen type IV (COL4) isoform ααα. The constituent COL4 α-chains assemble into heterotrimers in the endoplasmic reticulum before secretion into the extracellular space. If any one of the α-, α-, or α-chains is lost due to mutation of one of the genes, then the entire heterotrimer is lost. Patients with Alport syndrome typically have mutations in the X-linked COL4A5 gene or uncommonly have the autosomal recessive form of the disease due to COL4A3 or COL4A4 mutations. Treatment for Alport syndrome is currently limited to angiotensin-converting enzyme inhibition or angiotensin receptor blockers. Experimental approaches in Alport mice have demonstrated that induced expression of COL4A3, either widely or specifically in podocytes of Col4a3 mice, can abrogate disease progression even after establishment of the abnormal GBM. While targeting podocytes in vivo for gene therapy is a significant challenge, the more accessible glomerular endothelium could be amenable for mutant gene repair. In the present study, we expressed COL4A3 in Col4a3 Alport mice using an endothelial cell-specific inducible transgenic system, but collagen-ααα(IV) was not detected in the GBM or elsewhere, and the Alport phenotype was not rescued. Our results suggest that endothelial cells do not express the Col4a3/a4/a5 genes and should not be viewed as a target for gene therapy.