title: Conditional inactivation of the mouse von Hippel-Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney.
abstract: Mutations of the tumor suppressor gene von Hippel-Lindau (VHL) can lead to benign and malignant tumors, including clear-cell renal cell carcinoma (ccRCC). To understand the progression of ccRCC, we generated a novel mouse Vhlh conditional knockout, using Hoxb7-driven Cre that is specific for the collecting ducts and a subset of distal tubules. These mice exhibited wide-spread epithelial disruption and interstitial inflammation as early as 2 months of age with high penetrance. Lesions are cystic, show severe fibrosis and display significant hyperplasia. An abundance of infiltrating macrophages and lymphocytes was detected. Interestingly, the Vhlh mutant lesions could be rescued when Hif-1α, but not Hif-2α, was also knocked out. In addition, administration of a JAK1/2 kinase inhibitor alleviated the Vhlh knockout phenotypes. Taken together, these results suggest that HIF-1α-dependent inflammation and fibrosis may be an early event in the development of ccRCC.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Pritchett
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Bader
authors.affiliation: 1] Department of Medicine, Boston University School of Medicine, Boston, MA, USA [2] Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Henderson
authors.affiliation: 1] Department of Medicine, Boston University School of Medicine, Boston, MA, USA [2] Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taiwan.
authors.forename: T
authors.initials: T
authors.lastname: Hsu
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C494469:VHL protein, mouse