Figure 5. Succinate and the GPR91 signaling pathway in the retinas of STZ-induced diabetic rats. Each solid line and arrow denotes a step in an activating pathway. Succinate accumulation triggered by hyperglycemia activates GPR91 signaling, sequentially activating ERK1/2 and then upregulating COX-2 and PGE₂ expression, and later increasing VEGF release in retinal ganglion cells. The increase of VEGF induces retinal vascular dysfunction and plays a key role in the pathology of diabetic retinopathy. The long dashed line and vertical lines denotes a step in an inhibiting pathway. U0126 blocks the ERK1/2 signaling pathway and the downstream expression of COX-2, PGE₂, and VEGF. NS-398 blocks COX-2 and PGE₂ and decreases PGE₂-mediated VEGF synthesis.