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.
Beirowski
Bogdan
B
Medical Faculty University of Cologne, Medicine Clinic I, Hospital Merheim, Ostmerheimer Strasse 200, D-51109 Cologne, Germany.
Weber
Manfred
M
Gross
Oliver
O
D000375:Aging / Q000502:physiology; D000818:Animals; D024141:Collagen Type IV / Q000235:genetics*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000473:pathology*; D015433:Glomerulonephritis, Membranous / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008136:Longevity / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009394:Nephritis, Hereditary / Q000235:genetics*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024141:Collagen Type IV; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1