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 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.
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The authors thank D. Vukasovic for secretarial assistance and the Centre for Modelling Human Diseases for biochemical assays in the mice. We also thank B. Pressler (University of North Carolina at Chapel Hill) for performing ANCA assays, Y. Wang (Samuel Lunenfeld Research Institute) for help in LCM isolation, S. Peiper (Institute of Molecular Medicine and Genetics, Georgia) for providing the constitutively active Cxcr4 constructs, V. Eremina for technical assistance, K. Kamel (St. Michael's Hospital, Toronto) and D. Cattran (Toronto Hospital) for critically reviewing the manuscript. S.E.Q. is the recipient of a Canada Research Chair Tier II, and a Premier's Research of Excellence Award. This work was funded by Canadian Institute of Health Research grant MOP 77756, National Cancer Institute of Canada grant #16002 and Emerald Foundation grant (to S.E.Q.).
The authors declare no competing financial interests.
The renal glomerulus. (PDF 68 kb)
Generation of transgenic mouse lines. (PDF 340 kb)
PCNA staining. (PDF 94 kb)
Hif1a protein is increased in podocytes from VhlhloxP/loxP Pod-Cre mice. (PDF 165 kb)
Glomerular expression of Hif target genes. (PDF 259 kb)
Expression of the Hif target gene Sdf1 in glomeruli of wild-type and mutant mice. (PDF 119 kb)
Kaplan-Meier survival curves for mutant Vhlh mice treated with blocking antibody to Cxcr4 or vehicle. (PDF 48 kb)
mRNA expression analysis of VHL-HIF pathway molecular targets in glomeruli from patients with pauci-immune RPGN, IgA nephritis or no glomerular disease. (PDF 159 kb)
Gene expression patterns in human RPGN compared with expression in glomeruli from VhlhloxP/loxP Pod-Cre mice. (PDF 96 kb)
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