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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Falk, R.J., Terrell, R.S., Charles, L.A. & Jennette, J.C. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl. Acad. Sci. USA 87, 4115–4119 (1990).
Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).
Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).
Somlo, S. & Mundel, P. Getting a foothold in nephrotic syndrome. Nat. Genet. 24, 333–335 (2000).
Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).
Davies, D.J., Moran, J.E., Niall, J.F. & Ryan, G.B. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br. Med. J. (Clin. Res. Ed.) 285, 606 (1982).
Hedger, N., Stevens, J., Drey, N., Walker, S. & Roderick, P. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. Nephrol. Dial. Transplant. 15, 1593–1599 (2000).
Galban, S. et al. von Hippel-Lindau protein-mediated repression of tumor necrosis factor alpha translation revealed through use of cDNA arrays. Mol. Cell. Biol. 23, 2316–2328 (2003).
Timoshanko, J.R., Sedgwick, J.D., Holdsworth, S.R. & Tipping, P.G. Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis. J. Am. Soc. Nephrol. 14, 1785–1793 (2003).
Li, C.G. et al. Serum levels of vascular endothelial growth factor (VEGF) are markedly elevated in patients with Wegener's granulomatosis. Br. J. Rheumatol. 37, 1303–1306 (1998).
Sommer, M. et al. Rapidly progressive glomerulonephritis in a patient with advanced renal cell carcinoma. Nephrol. Dial. Transplant. 13, 2107–2109 (1998).
Kagan, A., Sinay-Trieman, L., Czernobilsky, B., Barzilai, N. & Bar-Khayim, Y. Is the association between crescentic glomerulonephritis and renal cell carcinoma coincidental? Nephron 65, 642–643 (1993).
Haase, V.H., Glickman, J.N., Socolovsky, M. & Jaenisch, R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc. Natl. Acad. Sci. USA 98, 1583–1588 (2001).
Moeller, M.J. et al. Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J. Am. Soc. Nephrol. 15, 61–67 (2004).
Novak, A., Guo, C., Yang, W., Nagy, A. & Lobe, C.G.Z. EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000).
Zagzag, D. et al. Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res. 65, 6178–6188 (2005).
Maynard, M.A. & Ohh, M. Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am. J. Nephrol. 24, 1–13 (2004).
Kucia, M. et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23, 879–894 (2005).
Grone, H.J. et al. Spatial and temporally restricted expression of chemokines and chemokine receptors in the developing human kidney. J. Am. Soc. Nephrol. 13, 957–967 (2002).
Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687–694 (2002).
Zhang, W.B. et al. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40–4C are weak partial agonists. J. Biol. Chem. 277, 24515–24521 (2002).
Belteki, G. et al. Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res. 33, e51 (2005).
Eremina, V., Wong, M.A., Cui, S., Schwartz, L. & Quaggin, S.E. Glomerular-specific gene excision in vivo. J. Am. Soc. Nephrol. 13, 788–793 (2002).
Cui, S., Li, C., Ema, M., Weinstein, J. & Quaggin, S.E. Rapid isolation of glomeruli coupled with gene expression profiling identifies downstream targets in Pod1 knockout mice. J. Am. Soc. Nephrol. 16, 3247–3255 (2005).
Wada, T., Pippin, J.W., Terada, Y. & Shankland, S.J. The cyclin-dependent kinase inhibitor p21 is required for TGF-beta1-induced podocyte apoptosis. Kidney Int. 68, 1618–1629 (2005).
Cohen, C.D., Frach, K., Schlondorff, D. & Kretzler, M. Quantitative gene expression analysis in renal biopsies: a novel protocol for a high-throughput multicenter application. Kidney Int. 61, 133–140 (2002).
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)
About this article
Cite this article
Ding, M., Cui, S., Li, C. et al. Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 12, 1081–1087 (2006). https://doi.org/10.1038/nm1460
The journey from erythropoietin to 2019 Nobel Prize: Focus on hypoxia-inducible factors in the kidney
Journal of the Formosan Medical Association (2021)
C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway
Journal of Cellular and Molecular Medicine (2020)
International Urology and Nephrology (2020)
Nephrology Dialysis Transplantation (2020)
Nature Reviews Nephrology (2019)