Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy

Table 2

Antioxidants depleted in diabetic retinopathy.

Antioxidants	Mechanism of action	Effect on DR
Thioredoxin (Trx)	The negative regulator of thioredoxin, thioredoxin-interacting protein (TXNIP), and the dissociation of apoptosis signal regulating kinase-1 (ASK-1) from the oxidised thioredoxin are key players inducing apoptosis during DR [140, 141].	ASK-1 induces apoptosis of Neuro2a cells during DR. TXNIP is upregulated in Muller cells and leads to apoptosis of pericytes [140, 142].
Superoxide dismutase (SOD)	First line of defence against hyperglycemic induced superoxide anion radicals in the mitochondria, and the highest SOD activity is present in the retina to help scavenge the superoxide radicals generated via metabolism [143–145].	SOD downregulation in retinal endothelial cells induces apoptosis [146] and upon overexpression ameliorates and protects the mtDNA from oxidative damage in DR [144].
NADPH oxidase (Nox)	Nox4, an isoform of Nox enzyme, promotes retinal neovascularization through ROS-dependent regulation of the VEGF/VEGFR2 signalling pathway [147] and via various inflammatory signalling pathways [148].	Nox4 isoform gene (NOX4) is involved in DR [149] and is the predominant isoform expressed in the human retinal endothelial cells [150].
Vitamin E (α-tocopherol)	A nonenzymatic antioxidant which donates hydrogen atom to peroxy radicals and other radicals to maintain the redox status of the cell [151].	Its supplementation reduces oxidative stress in NPDR and PDR patients [152] interlinking an antioxidant role in the prevention of DR.
Vitamin C (ascorbic acid)	An antioxidant or a reducing agent that donates electrons to various radical species [153].	Prevents high-glucose and RAGE-induced apoptosis in pericytes and endothelial cells. Also preserves NO generated by endothelial cells and tightens the leaky endothelial permeability barrier [154].