Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice

Mei Ding, Shiying Cui, Chengjin Li, Serge Jothy, Volker Haase, Brent M. Steer, Philip A. Marsden, Jeffrey Pippin, Stuart Shankland, Maria Pia Rastaldi, Clemens D. Cohen, Matthias Kretzler, Susan E. Quaggin*

*Corresponding author for this work

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors are believed to have a major role. Here, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor α subunits (HIFs). Using gene expression profiling, we identified de novo expression of the HIF target gene Cxcr4 (ref. 3) in glomeruli from both mice and humans with RPGN. The course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease.

Original languageEnglish (US)
Pages (from-to)1081-1087
Number of pages7
JournalNature Medicine
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ding, M., Cui, S., Li, C., Jothy, S., Haase, V., Steer, B. M., Marsden, P. A., Pippin, J., Shankland, S., Rastaldi, M. P., Cohen, C. D., Kretzler, M., & Quaggin, S. E. (2006). Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nature Medicine, 12(9), 1081-1087. https://doi.org/10.1038/nm1460