Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model
Ana Martins Metelo, … , Randall T. Peterson, Othon Iliopoulos
Ana Martins Metelo, … , Randall T. Peterson, Othon Iliopoulos
Published April 13, 2015
Citation Information: J Clin Invest. 2015;125(5):1987-1997. https://doi.org/10.1172/JCI73665.
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Research Article Oncology

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

Abstract

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.

Authors

Ana Martins Metelo, Haley R. Noonan, Xiang Li, Youngnam Jin, Rania Baker, Lee Kamentsky, Yiyun Zhang, Ellen van Rooijen, Jordan Shin, Anne E. Carpenter, Jing-Ruey Yeh, Randall T. Peterson, Othon Iliopoulos

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Figure 6

HIF2α inhibitor compound 76 rescues cardiac contractility of vhl–/– embryos and improves their early lethality.

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HIF2α inhibitor compound 76 rescues cardiac contractility of vhl–/– embr...
(A) Quantification of ventricular fractional shortening, a measurement of cardiac performance, in 5-dpf WT and vhl–/– embryos treated with compound 76 for 48 hours (n = 12). *P < 0.05, 1-way ANOVA. (B) vhl–/– embryos were selected at 3 dpf and treated with compound 76 or vehicle-only control, until death (n = 30). Each experiment was repeated 4 times. The percentage of dead embryos over time is presented. Data represent mean ± SEM. *P < 0.05, paired, 2-tailed t test.