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This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2005101044v1 17/7/1986    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beirowski, B. Articles by Gross, O. Search for Related Content PubMed PubMed Citation Articles by Beirowski, B. Articles by Gross, O.

Chronic Renal Failure and Shortened Lifespan in COL4A3^+/– Mice: An Animal Model for Thin Basement Membrane Nephropathy

Medical Faculty University of Cologne, Medicine Clinic I, Hospital Merheim, Cologne, Germany

Address correspondence to: Dr. Oliver Gross, Medical Faculty University of Cologne, Medicine Clinic I, Hospital Merheim, Ostmerheimer Strasse 200, D-51109 Cologne, Germany. Phone: +49-221-8907-3200; Fax: +49-221-8907-3335; oliver.gross{at}uni-koeln.de

Received for publication October 10, 2005. Accepted for publication April 22, 2006.

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- 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673