This study aimed to assess a potential role of hypoxia triggered genes for the development and recruitment of renin producing cells in the kidney. The stability of hypoxia-inducible transcription factors (HIF), key mediators of the transcriptional response to hypoxia, is tightly controlled by the tumor suppressor von Hippel-Lindau (VHL). Therefore Vhl was conditionally deleted using the Cre/loxP system with renin-1d promoter driven Cre expression. Vhl ^-/-REN mice were viable and had normal blood pressure. Deletion of Vhl resulted in constitutive accumulation of HIF-2α in afferent arterioles and glomerular cells and of HIF-1α in collecting duct cells of the adult kidney. The preglomerular vascular tree was normally developed, but renin expressing cells were strongly reduced in number. More than 70% of the glomeruli did not contain renin cells at the typical juxtaglomerular position. Moreover, the expansion of renin producing cells in response to low-salt diet combined with an angiotensin-I converting enzyme inhibitor was strongly inhibited. Following Vhl deletion renin producing cells did however express the erythropoietin gene and Vhl ^-/-REN mice were markedly polycythemic (hct 69% vs. 47 in Vhl ^fl/fl mice). We infer from our results that VHL is essential for normal development and physiologic adaptation of renin producing cells and that Vhl deletion, presumably through accumulation of HIF-2 causes a phenotype shift of juxtaglomerular cells from the renin secreting to an erythropoietin secreting cell type.