Nephrin TRAP Mice Lack Slit Diaphragms and Show Fibrotic Glomeruli and Cystic 
Tubular Lesions

Rantanen, Maija; Palmén, Tuula; Pätäri, Anu; Ahola, Heikki; Lehtonen, Sanna; Åström, Eva; Floss, Thomas; Vauti, Franz; Wurst, Wolfgang; Ruiz, Patrizia; Kerjaschki, Dontscho; Holthöfer, Harry

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Nephrin TRAP Mice Lack Slit Diaphragms and Show Fibrotic Glomeruli and Cystic Tubular Lesions

Rantanen, M., Palmén, T., Pätäri, A., Ahola, H., Lehtonen, S., Åström, E., et al. (2002). Nephrin TRAP Mice Lack Slit Diaphragms and Show Fibrotic Glomeruli and Cystic Tubular Lesions. Journal of the American Society of Nephrology, 13, 1586-1594.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-8C4A-5 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-8C4B-3

Genre: Journal Article

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Rantanen, Maija, Author
Palmén, Tuula, Author
Pätäri, Anu, Author
Ahola, Heikki, Author
Lehtonen, Sanna, Author
Åström, Eva, Author
Floss, Thomas, Author
Vauti, Franz, Author
Wurst, Wolfgang, Author
Ruiz, Patrizia¹, Author
Kerjaschki, Dontscho, Author
Holthöfer, Harry, Author

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1Max Planck Society, ou_persistent13

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Abstract: The molecular mechanisms maintaining glomerular filtration barrier are under intensive study. This study describes a mutant Nphs1 mouse line generated by gene-trapping. Nephrin, encoded by Nphs1, is a structural protein of interpodocyte filtration slits crucial for formation of primary urine. Nephrintrap/trap mutants show characteristic features of proteinuric disease and die soon after birth. Morphologically, fibrotic glomeruli with distorted structures and cystic tubular lesions were observed, but no prominent changes in the branching morphogenesis of the developing collecting ducts could be found. Western blotting and immunohistochemical analyses confirmed the absence of nephrin in nephrintrap/trap glomeruli. The immunohistochemical staining showed also that the interaction partner of nephrin, CD2-associated protein (CD2AP), and the slit-diaphragm-associated protein, ZO-1 -, appeared unchanged, whereas the major anionic apical membrane protein of podocytes, podocalyxin, somewhat punctate as compared with the wild-type (wt) and nephrinwt/trap stainings. Electron microscopy revealed that >90% of the podocyte foot processes were fused. The remaining interpodocyte junctions lacked slit diaphragms and, instead, showed tight adhering areas. In the heterozygote glomeruli, approximately one third of the foot processes were fused and real-time RT-PCR showed >60% decrease of nephrin-specific transcripts. These results show an effective nephrin gene elimination, resulting in a phenotype that resembles human congenital nephrotic syndrome. Although the nephrintrap/trap mice can be used to study the pathophysiology of the disease, the heterozygous mice may provide a useful model to study the gene dose effect of this crucial protein of the glomerular filtration barrier.

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Language(s): eng - English

Dates: Date issued: 2002-02-23

Publication Status: Issued

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Identifiers: eDoc: 27205

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Title: Journal of the American Society of Nephrology

Source Genre: Journal

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Pages: - Volume / Issue: 13 Sequence Number: - Start / End Page: 1586 - 1594 Identifier: -