Endothelial cell-specific collagen type IV-α3 expression does not rescue Alport syndrome in Col4a3-/- mice.

Abstract

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 α3α4α5. The constituent COL4 α-chains assemble into heterotrimers in the endoplasmic reticulum before secretion into the extracellular space. If any one of the α3-, α4-, or α5-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-α3α4α5(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.

• Authors: Steven D Funk, Raymond H Bayer, Jeffrey H Miner
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 316 Issue 5 Pg. F830-F837 (05 01 2019) ISSN: 1522-1466 [Electronic] United States
• PMID: 30724107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Autoantigens
• Col4a1 protein, mouse
• Col4a5 protein, mouse
• Collagen Type IV
• Protein Subunits
• type IV collagen alpha3 chain

Topics

• Animals
• Autoantigens (genetics, metabolism)
• Collagen Type IV (deficiency, genetics, metabolism)
• Disease Models, Animal
• Endothelial Cells (metabolism, pathology)
• Genetic Predisposition to Disease
• Genetic Therapy
• Kidney Glomerulus (blood supply)
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Knockout
• Nephritis, Hereditary (genetics, metabolism, pathology, therapy)
• Phenotype
• Protein Subunits