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

Nature Medicine volume 12, pages 1081–1087 (2006)Cite this article

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 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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Figure 1: Selective deletion of Vhlh from podocytes leads to RPGN.
Figure 2: Podocyte proliferation initiates crescent formation.
Figure 3: Increased Cxcr4 is functionally important for the RPGN phenotype.
Figure 4: De novo expression of CXCR4 in mice and humans with glomerular disease.

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References

  1. 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).

    Article  CAS  Google Scholar 

  2. Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955–963 (2002).

    Article  CAS  Google Scholar 

  3. Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).

    Article  CAS  Google Scholar 

  4. Somlo, S. & Mundel, P. Getting a foothold in nephrotic syndrome. Nat. Genet. 24, 333–335 (2000).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Sommer, M. et al. Rapidly progressive glomerulonephritis in a patient with advanced renal cell carcinoma. Nephrol. Dial. Transplant. 13, 2107–2109 (1998).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Moeller, M.J. et al. Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J. Am. Soc. Nephrol. 15, 61–67 (2004).

    Article  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. 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).

    Article  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.).

Author information

Author notes

  1. Matthias Kretzler

    Present address: Division of Nephrology, Department of Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109-0676, USA

Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Mei Ding, Shiying Cui, Chengjin Li & Susan E Quaggin

  2. Institute of Medical Science, 7213 Medical Sciences Building, 1 King's College Circle, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Mei Ding & Susan E Quaggin

  3. Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, M5B 1W8, Ontario, Canada

    Serge Jothy

  4. Department of Medicine, Program in Cell Growth and Cancer, University of Pennsylvania, 3451 Walnut Street, Philadelphia, 19104, Pennsylvania, USA

    Volker Haase

  5. Department of Medicine and Division of Nephrology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, M5B 1W8, Ontario, Canada

    Brent M Steer, Philip A Marsden & Susan E Quaggin

  6. Division of Nephrology, University of Washington, 1959 NE Pacific Street, Box 356521, Seattle, 98195, Washington, USA

    Jeffrey Pippin & Stuart Shankland

  7. Renal Immunopathology Laboratory, Fondazione D'Amico per la Ricerca sulle Malattie Renali, c/o San Carlo Hospital, via Pio II, 3, Milan, 20153, Italy

    Maria Pia Rastaldi

  8. Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-Universität München, Pettenkoferstr. 8a, Munich, 80336, Germany

    Clemens D Cohen & Matthias Kretzler

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Correspondence to Susan E Quaggin.

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Supplementary information

Supplementary Fig. 1

The renal glomerulus. (PDF 68 kb)

Supplementary Fig. 2

Generation of transgenic mouse lines. (PDF 340 kb)

Supplementary Fig. 3

PCNA staining. (PDF 94 kb)

Supplementary Fig. 4

Hif1a protein is increased in podocytes from VhlhloxP/loxP Pod-Cre mice. (PDF 165 kb)

Supplementary Fig. 5

Glomerular expression of Hif target genes. (PDF 259 kb)

Supplementary Fig. 6

Expression of the Hif target gene Sdf1 in glomeruli of wild-type and mutant mice. (PDF 119 kb)

Supplementary Fig. 7

Kaplan-Meier survival curves for mutant Vhlh mice treated with blocking antibody to Cxcr4 or vehicle. (PDF 48 kb)

Supplementary Fig. 8

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)

Supplementary Table 1

Gene expression patterns in human RPGN compared with expression in glomeruli from VhlhloxP/loxP Pod-Cre mice. (PDF 96 kb)

Supplementary Note (PDF 29 kb)

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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

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