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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 α 3 α 4 α 5 . The constituent COL4 α-chains assemble into heterotrimers in the endoplasmic reticulum before secretion into the extracellular space. If any one of the α 3 -, α 4 -, or α 5 -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-α 3 α 4 α 5 (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.

Endothelial cell-specific collagen type IV-α3expression does not rescue Alport syndrome inCol4a3−/−mice

Endothelial cell-specific collagen type IV-α₃expression does not rescue Alport syndrome inCol4a3⁻^/−mice