The purpose of the HIF-1/PHD feedback loop To limit mTOR-induced HIF-1α

Prolyl hydroxylases (PHDs) target hypoxia-inducible factor-1 alpha (HIF-1 alpha) for degradation. Hypoxia inactivates PHDs, causing accumulation of HIF-1 alpha. In turn, HIF-1 further transactivates PHDs. It is thought that the purpose of this feedback loop is to limit HIF-1 alpha accumulation caused by hypoxia. Here, we suggest that the feedback is intended to limit the induction of HIF-1 alpha by insulin, growth factors, hormones, cytokines and nutrients. These stimuli induce HIF-1 alpha by increasing its translation, not by inhibiting PHDs. As exemplified herein, in a mTOR-dependent manner, insulin transiently induced HIF-1 alpha in retinal pigment epithelial (RPE) cells. Induction of HIF-1 alpha was followed by activation of HIF-dependent transcription. Furthermore, DFX, which inactivates PHDs, potentiated the induction of HIF-1 alpha by insulin. We discuss that the most relevant function of the PHD-HIF feedback loop is to limit the induction of HIF-1 alpha by mTOR. The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases.