Hypoxia Induces Activity of both Efflux and Influx Transporters in Retinal Epithelial Cells

Introduction A continuous oxygen supply is pivotal for tissue development, regeneration, proper maintenance, and homeostasis of the body. During oxidative phosphorylation oxygen (O2) is necessary for the cells to produce ATP. This process produces higher energy than glycolysis. O2 is an essential element for cell survival, membrane transport, regulation of cell signaling, and gene expression. Deficiency of O2 (hypoxia ≈1%) occurs when cellular O2 supply from the blood is insufficient than demand. O2 is supplied through the circulation by erythrocytes and its production is regulated by hormone/ growth factor called erythropoietin (EPO), the product of liver and kidney. EPO supply is inversely proportional to blood O2 level. During hypoxia EPO is stimulated promoting red blood cells production enhancing O2 transport capacity. Also, response to reduced tissue O2 level is mediated by specific transcriptional regulator called hypoxia-inducible factor-1 (HIF1). HIF-1A gene is encoded on 14q21-q24 human chromosome. The Heterodimeric HIF-1 comprises an O2 dependent nuclear subunit (HIF1-α) and a constitutively expressed O2 independent subunit HIF1-β. The HIF1-β is also recognized as aryl-hydrocarbon receptor nuclear translocator (ARNT). Both subunits belong to basic helix-loop-helix (bHLH-PAS) proteins family [1]. HIF-1 can induce transcription of more than 60 genes including vascular endothelial growth factor (VEGF) and erythropoietin resulting in angiogenesis and erythropoiesis respectively [2]. In normoxic conditions, HIF1-α synthesized de novo is degenerated by 26S proteasome, whereas in hypoxia this HIF1-α is stabilized by joining the HIF1-β resulting in transcriptional activation of several genes. These target genes are involved in regulation of cell survival, angiogenesis, cellular proliferation, invasion, genetic instability, metastasis, immortalization, radiation and chemotherapy resistance, and stem cell maintenance [3].