NADPH oxidase: A membrane-bound enzyme and its inhibitors in diabetic complications.

ABSTRACT

The human body has a mechanism for balancing the generation and neutralization of reactive oxygen species. The body is exposed to many agents that are responsible for the generation of reactive oxygen/nitrogen species, which leads to disruption of the balance between generation of these species and oxidative stress defence mechanisms. Diabetes is a chronic pathological condition associated with prolonged hyperglycaemia. Prolonged elevation of level of glucose in the blood leads to the generation of reactive oxygen species. This generation of reactive oxygen species is responsible for the development of diabetic vasculopathy, which includes micro- and macrovascular diabetic complications. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a membrane-bound enzyme responsible for the development of reactive oxygen species in hyperglycaemia. Phosphorylation of the cytosolic components of NOX, such as p47phox, p67phox, and RAC-1, in hyperglycaemia is one of the important causes of conversion of oxygen to reactive oxygen. Overexpression of NOX in pathological conditions is associated with activation of aldose reductase, advanced glycation end products, protein kinase C and the hexosamine pathway. In addition, NOX also promotes the activation of inflammatory cytokines, such as TGF-ß, TNF-α, NF-kß, IL-6, and IL-18, the activation of endothelial growth factors, such as VEGF and FGF, hyperlipidaemia, and the deposition of collagen. Thus, overexpression of NOX is linked to the development of diabetic complications. The present review focuses on the role of NOX, its associated pathways, and various NOX inhibitors in the management and treatment of diabetic complications, such as diabetic nephropathy, retinopathy, neuropathy and cardiomyopathy.