Formation Of Renal Cysts And Tumors In Vhl/Trp53-Deficient Mice Requires Hif1 Alpha And Hif2 Alpha

The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1 alpha has been implicated as a renal tumor suppressor, whereas HIF2 alpha is considered an oncoprotein. In this study, we investigated the contributions of HIF1 alpha and HIF2 alpha to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1 alpha or Hif2 alpha specifically in the renal epithelium did not induce tumor formation. However, HIF1 alpha and HIF2 alpha differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1 alpha, but not HIF2 alpha, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1 alpha or Hif2 alpha completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1 alpha and HIF2 alpha exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney.