title: Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice.
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 role. 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 alpha 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Mei
authors.initials: M
authors.lastname: Ding
authors.forename: Shiying
authors.initials: S
authors.lastname: Cui
authors.forename: Chengjin
authors.initials: C
authors.lastname: Li
authors.forename: Serge
authors.initials: S
authors.lastname: Jothy
authors.forename: Volker
authors.initials: V
authors.lastname: Haase
authors.forename: Brent M
authors.initials: BM
authors.lastname: Steer
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Pippin
authors.forename: Stuart
authors.initials: S
authors.lastname: Shankland
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D005921:Glomerulonephritis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C514936:CXCR4 protein, mouse; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse