期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 316, 期 5, 页码 F830-F837出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00556.2018
关键词
Alport syndrome; collagen type IV; gene therapy; glomerular basement membrane; transgenic mouse
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-078314, T32-D-K007126]
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 (COLA) isoform alpha(3),alpha(4),alpha(5). The constituent COL4 alpha-chains assemble into heterotrimers in the endoplasmic reticulum before secretion into the extracellular space. If any one of the alpha(3)-,alpha(4)- or alpha(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-alpha(3)alpha(4)alpha(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.
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