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Collagen alpha-4(IV) chain precursor


Chronic renal failure and shortened lifespan in COL4A3 /- mice: an animal model for thin basement membrane nephropathy.

A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3( /-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3( /-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3( /-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3( /-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.

MeSH Terms

  • Aging
  • Animals
  • Collagen Type IV
  • Disease Models, Animal
  • Extracellular Matrix
  • Glomerular Basement Membrane
  • Glomerulonephritis, Membranous
  • Kidney
  • Kidney Failure, Chronic
  • Longevity
  • Mice
  • Mice, Transgenic
  • Nephritis, Hereditary
  • Phenotype
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1

Tissue- and developmental stage-specific activation of alpha 5 and alpha 6(IV) collagen expression in the upper gastrointestinal tract of transgenic mice.

Little is known about mechanisms regulating gene expression for the alpha chains of basement membrane type IV collagen, arranged head-to-head in transcription units COL4A1-COL4A2, COL4A3-COL4A4, and COL4A5-COL4A6, and implicated broadly in genetic diseases. To investigate these mechanisms, we generated transgenic mouse lines bearing 5'-flanking sequences of COL4A5 and COL4A6, cloned upstream of a lacZ reporter gene. A 3.8-kb fragment upstream of COL4A6 directs reporter gene expression in the esophagus, stomach, and duodenum, whereas a 13.8-kb fragment directs expression in the esophagus only. A 10.6-kb fragment upstream of COL4A5 directs expression in the esophagus. Coupled with evidence of long-range conservation between human and mouse non-coding sequences, described herein, our findings provide the first indication that highly specialized patterns characteristic of COL4A5-COL4A6 expression in vivo arise from effects of distributed cis-acting regulatory elements on a bidirectional proximal promoter, itself transcriptionally competent.

MeSH Terms

  • Aging
  • Amino Acid Sequence
  • Animals
  • Collagen Type IV
  • Gene Expression Regulation
  • Genes, Regulator
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Organ Specificity
  • Protein Subunits
  • Sequence Homology
  • Species Specificity
  • Tissue Distribution
  • Transcriptional Activation
  • Upper Gastrointestinal Tract