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

Mei Ding^1, 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 Kretzler^8, 9 & Susan E Quaggin^1, 2, 5

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

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

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

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

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

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

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.

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

⁹  Current address: Division of Nephrology, Department of Medicine, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0676,USA.

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^{1, 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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