| First Author | Funk SD | Year | 2019 |
| Journal | Am J Physiol Renal Physiol | Volume | 316 |
| Issue | 5 | Pages | F830-F837 |
| PubMed ID | 30724107 | Mgi Jnum | J:278133 |
| Mgi Id | MGI:6355890 | Doi | 10.1152/ajprenal.00556.2018 |
| Citation | Funk SD, et al. (2019) Endothelial cell-specific collagen type IV-alpha3 expression does not rescue Alport syndrome in Col4a3(-)(/-) mice. Am J Physiol Renal Physiol 316(5):F830-F837 |
| abstractText | 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 alpha3alpha4alpha5. The constituent COL4 alpha-chains assemble into heterotrimers in the endoplasmic reticulum before secretion into the extracellular space. If any one of the alpha3-, alpha4-, or alpha5-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-alpha3alpha4alpha5(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. |
