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.
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Acknowledgements
Paraffin embedding and sectioning were performed at the Immunohistochemistry Core of Boston Medical Center. We thank Richard Near (the Boston University School of Medicine) for technical support and Weining Lu (the Boston University School of Medicine) for a gift of the Hoxb7–Cre–EGFP mouse strain. This work was supported by a grant to TH from the National Institutes of Health, USA (#R01CA109860) and a postdoctoral fellowship to HLB from the National Institutes of Health, USA (#T32HL007501).
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Pritchett, T., Bader, H., Henderson, J. et al. Conditional inactivation of the mouse von Hippel–Lindau tumor suppressor gene results in wide-spread hyperplastic, inflammatory and fibrotic lesions in the kidney. Oncogene 34, 2631–2639 (2015). https://doi.org/10.1038/onc.2014.197
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DOI: https://doi.org/10.1038/onc.2014.197
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