Endothelial cell-specific collagen type IV-α 3 expression does not rescue Alport syndrome in Col4a3 -/- mice

Am J Physiol Renal Physiol. 2019 May 1;316(5):F830-F837. doi: 10.1152/ajprenal.00556.2018. Epub 2019 Feb 6.

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.

Keywords: Alport syndrome; collagen type IV; gene therapy; glomerular basement membrane; transgenic mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

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