title: Vhl deletion in renal epithelia causes HIF-1α-dependent, HIF-2α-independent angiogenesis and constitutive diuresis.
abstract: One of the earliest requirements for the formation of a solid tumor is the establishment of an adequate blood supply. Clear cell renal cell carcinomas (ccRCC) are highly vascularized tumors in which the earliest genetic event is most commonly the biallelic inactivation of the VHL tumor suppressor gene, leading to constitutive activation of the HIF-1α and HIF-2α transcription factors, which are known angiogenic factors. However it remains unclear whether either or both HIF-1α or HIF-2α stabilization in normal renal epithelial cells are necessary or sufficient for alterations in blood vessel formation. We show that renal epithelium-specific deletion of Vhl in mice causes increased medullary vascularization and that this phenotype is completely rescued by Hif1a co-deletion, but not by co-deletion of Hif2a. A physiological consequence of changes in the blood vessels of the vasa recta in Vhl-deficient mice is a diabetes insipidus phenotype of excretion of large amounts of highly diluted urine. This constitutive diuresis is fully compensated by increased water consumption and mice do not show any signs of dehydration, renal failure or salt wasting and blood electrolyte levels remain unchanged. Co-deletion of Hif1a, but not Hif2a, with Vhl, fully restored kidney morphology and function, correlating with the rescue of the vasculature. We hypothesize that the increased medullary vasculature alters salt uptake from the renal interstitium, resulting in a disruption of the osmotic gradient and impaired urinary concentration. Taken together, our study characterizes a new mouse model for a form of diabetes insipidus and non-obstructive hydronephrosis and provides new insights into the physiological and pathophysiological effects of HIF-1α stabilization on the vasculature in the kidney.
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Désirée
authors.initials: D
authors.lastname: Schönenberger
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Rajski
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Harlander
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Frew
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000652:urine; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000652:urine; D004231:Diuresis; D004573:Electrolytes; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D006869:Hydronephrosis / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000652:urine; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009389:Neovascularization, Pathologic; D010641:Phenotype; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014556:Urine; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism* / Q000652:urine; D055114:X-Ray Microtomography; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004573:Electrolytes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse
keywords: HIF-α; VHL; angiogenesis; diuresis; kidney