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. 2019 Mar 29;10:300. doi: 10.3389/fphar.2019.00300

FIGURE 8.

FIGURE 8

Schematic diagram showing how B1R and iNOS can partake in a mutual auto-induction and amplification loop to enhance nitrogen species formation and inflammation in diabetic retina. B1R agonists enhance the formation of peroxynitrite (ONOO-) through the activation of iNOS and NADPH oxidase pathways. iNOS activation produces high amount of NO while NADPH oxidase activation leads to superoxide anion (O2∙-) formation that can rapidly react with NO to form ONOO-. Peroxynitrite formation induces an inflammatory response, enhances the oxidative stress and vascular permeability, neovascularization and retinal hemorrhage. Both O2∙- and ONOO- are known to activate the transcriptional nuclear factor, NF-κB, which is involved in the transcription of several inflammatory genes, notably iNOS, B1R, and CPM. iNOS inhibitor (1400W) and B1R antagonists prevent this vicious cycle and the pro-inflammatory effect of B1R.