Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model

Martins Metelo, A., Noonan, H.R., Xiang, L., Jin, Y., Baker, R., Kamentsky, L., Zhang, Y., van Rooijen, E., Shin, J., Carpenter, A.E., Yeh, J.R., Peterson, R.T., Iliopoulos, O.
J. Clin. Invest.   125(5): 1987-97 (Journal)
Registered Authors
Peterson, Randall, Shin, Jordan, van Rooijen, Ellen, Yeh, Jing-Ruey (Joanna)
MeSH Terms
  • 5' Untranslated Regions
  • Amino Acids, Dicarboxylic/toxicity
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors*
  • Basic Helix-Loop-Helix Transcription Factors/deficiency
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Brain/blood supply
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Embryo, Nonmammalian
  • Gene Expression Regulation/drug effects
  • Humans
  • Hydrazones/pharmacology
  • Hydrazones/therapeutic use*
  • Hypoxia-Inducible Factor 1, alpha Subunit/deficiency
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Kidney/pathology
  • Liver/pathology
  • Myocardial Contraction/drug effects
  • Neovascularization, Pathologic/drug therapy
  • Neovascularization, Pathologic/genetics
  • Phenotype
  • Polycythemia/drug therapy
  • Polycythemia/genetics
  • Retinal Vessels/pathology
  • Sulfones/pharmacology
  • Sulfones/therapeutic use*
  • Tumor Suppressor Proteins/deficiency
  • Tumor Suppressor Proteins/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • von Hippel-Lindau Disease/drug therapy*
  • von Hippel-Lindau Disease/genetics
  • von Hippel-Lindau Disease/pathology
  • von Hippel-Lindau Disease/physiopathology
25866969 Full text @ J. Clin. Invest.
Patients with a germline mutation in von Hippel-Lindau (VHL) develop renal cell cancers and hypervascular tumors of the brain, adrenal glands, and pancreas as well as erythrocytosis. These phenotypes are driven by aberrant expression of HIF2α, which induces expression of genes involved in cell proliferation, angiogenesis, and red blood cell production. Currently, there are no effective treatments available for VHL disease. Here, using an animal model of VHL, we report a marked improvement of VHL-associated phenotypes following treatment with HIF2α inhibitors. Inactivation of vhl in zebrafish led to constitutive activation of HIF2α orthologs and modeled several aspects of the human disease, including erythrocytosis, pathologic angiogenesis in the brain and retina, and aberrant kidney and liver proliferation. Treatment of vhl-/- mutant embryos with HIF2α-specific inhibitors downregulated Hif target gene expression in a dose-dependent manner, improved abnormal hematopoiesis, and substantially suppressed erythrocytosis and angiogenic sprouting. Moreover, pharmacologic inhibition of HIF2α reversed the compromised cardiac contractility of vhl-/- embryos and partially rescued early lethality. This study demonstrates that small-molecule targeting of HIF2α improves VHL-related phenotypes in a vertebrate animal model and supports further exploration of this strategy for treating VHL disease.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes