*4.4.2.2 Hypoxia inducible factor*

Adapting to hypoxic conditions leads to cellular and tissue transcriptional induction involving genes that participate in angiogenesis, glucose metabolism, and cell proliferation and survival. The principal factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. It consists of a constitutively expressed subunit HIF-1β and an oxygen-regulated subunit HIF-1α [82]. It has been shown that diabetic factors result in HIF-1 production and angiogenesis and Treins et al. [83] showed that insulin-like growth factor-1 (IGF-1) stimulates accumulation of HIF-1 in human retinal pigment epithelial cells. As HIF-1 becomes active it activates several genes, including the genes for IL-6, IL-8, and pro-angiogenic growth factors. It has also been shown that acute intensive insulin therapy exacerbates the diabetic induced BRB breakdown through HIF-1 and VEGF [84] and presence of HIF-1α has been demonstrated in diabetic epiretinal membrane [85]. NF-κB controls the expression and synthesis of HIF-1 in response to inflammatory stimuli. Hypoxia activates NF-κB that binds promoter of HIF-1, stimulates the production of IL-6 and IL-8 in the vitreous of patients with PDR. HIF-1α, Ang-2 and VEGF seem to play an important role in the pathogenesis of PDR and simultaneously provide adverse angiogenic milieu in PDR epiretinal membranes favouring aberrant neovascularisation and endothelial abnormalities [84].
