*4.4.2.1 Nuclear factor kappa beta (NF-*κ*B)*

NF-κB is a pro inflammatory transcription factor and a regulator of inflammation related to immune responses, cellular proliferation and cell apoptosis [76]. It is located in endothelial and retinal pericytes and released on exposure to hypoxia and hyperglycemia and thereafter releases cytokines, chemokines, and other pro-inflammatory molecules [59]. Once NF-κB is activated it leads to production of cytokines, chemokines and other pro-inflammatory molecules [77]. Studies have shown a relation between NF-κB activation and downstream up-regulation of vascular endothelial growth factor (VEGF) in DR. VEGF SNPs i.e., RS2010963 C allele and RS3025039 T allele might be strongly associated with PDR occurrence and in turn regulating VEGF expression in PDR subjects [78]. NF-κB is also involved in the formation of both glial and vascular endothelial cellular components, and that these two cell types might have functional interactions that lead to the enlargement of intraocular proliferative membranes namely ERM [79]. Receptor activator of NF-κB ligand (RANKL) is a member of the tumour necrosis factor (TNF) superfamily. RANKL increases endothelial permeability and induces angiogenesis, suggesting its critical roles in the vasculature. Hence the use of an RANKL blockade as a potential therapeutic approach against ischemic retinopathies is confirmed [80]. It is important to remember that the signal related to RANKL plays a role in

the pathogenesis of insulin resistance and suggests a link between inflammation and the pathogenesis of type 2 diabetes mellitus [81].
