Figure 8. Schematic summary of signal transduction pathways that are implicated in regulation of expression of the OPN gene in cultured RPE cells under hyperosmotic and hypoxic conditions. A: High NaCl-induced extracellular hyperosmolarity induces release of VEGF, TGF-β1, FGF, IL-1β, and ATP from the cells. The first three factors inhibit, and IL-1β and ATP stimulate, OPN gene expression. The effect of ATP is mediated in part by autocrine or paracrine activation of the P2Y₂ receptors. Hyperosmotic OPN gene expression is mediated by the activities of p38 MAPK, ERK1/2, and PLA₂, and the transcriptional activities of CREB and NFAT5. Inhibitory effects on hyperosmotic expression of the OPN gene are mediated (in part) by JAK2 and AP-1. High NaCl, but not extracellular hyperosmolarity, also stimulates the secretion of the OPN protein from RPE cells. B: Hypoxia induces release of VEGF, IL-1β, and ATP from the cells. VEGF and IL-1β inhibit OPN gene expression. ATP is extracellularly degraded to adenosine which activates A₁ receptors resulting in stimulation of OPN gene expression. Hypoxic expression of the OPN gene is mediated (in part) by the activities of PI3K, PLA₂, and caspases. Inhibitory effects on hypoxic expression of the OPN gene are (in part) mediated by CREB and AP-1.