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Letter
Nature Medicine 12, 1081 - 1087 (2006)
Published online: 13 August 2006 | doi:10.1038/nm1460
Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice
Mei Ding1,2, Shiying Cui1, Chengjin Li1, Serge Jothy3, Volker Haase4, Brent M Steer5, Philip A Marsden5, Jeffrey Pippin6, Stuart Shankland6, Maria Pia Rastaldi7, Clemens D Cohen8, Matthias Kretzler8,9 & Susan E Quaggin1,2,5
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 role1, 2. 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 
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.
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