15th September 2018, Dr Chee L Khoo
Noxious family members?
When phagocytes engulf microorganisms, intracellular phagasome bound NADPH oxidase catalysed the production of reactive oxygen species (ROS) like superoxide and hydrogen perixoide which kills the microorganism. NADPH oxidase is also expressed on membranes of many other non-phagocytic cells. ROS play a pivotal role in many physiological processes including host defence, hormone biosynthesis, fertilisation and cellular signalling. Altered production of ROS has been implicated in the development of immune-deficiency, cardiovascular and renal pathologies.
In the last few years several non-phagocytic NADPH oxidase enzymes have been identified in all sorts of diverse tissues including vascular, renal and gastrointestinal cells. These enzymes show a high degree of homology to the phagocytic NADPH oxidase and are now designated the Nox family of NADPH oxidases.
The Nox family of homologues have 7 members – Nox 1 to 5 and Duox 1 and Duox 2. Nox 1 and Nox 2 are closely related in their function and are the most studied and their function most understood. Nox 3 is primarily found in the inner ear although it is also found in foetal lung, liver, kidney and spleen. Nox 5 is primarily found in lymphoid tissue and is thought to have an important role in lymphocyte signalling. Nox 5 is also found in glomerular cells and is thought to have a role in oxidative damage in diabetic nephropathy. It is also thought to have a regulatory role in spermatogenesis. Duox 1 and 2 are primarily found in thyroid tissue and is thought to a role in thyroid hormone synthesis.
Evidence suggests that among the seven Nox homologues, it is the Nox 1 and Nox 4 homologues that play a central role in the damaging effects of high glucose in cultured cells and contributes to hyperglycemia-mediated microvascular and macrovascular complications of diabetes in the retina, vasculature, heart, and kidney.
Nox homologues are located across the cell membranes and are binding sites for NADPH, flavin adenine dinucleotide (FAD), and heme. These membrane spanning centres pass electrons to form oxygen superoxide or hydrogen peroxide. Nox1 and Nox 2 requires p22phox to be activated and stabilised before binding to p47phox for their action. Nox 4 does not appear to require p47phox for its activity. The Nox homologues respond to various stimuli including hyperglycaemia, transforming growth factor beta, angiotensin II, insulin growth factors (IGF 1) and advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). These products are recognised as mediators of diabetic nephropathy.
Studies in experimental rodent models of diabetes and cultured cells exposed to high glucose showed that Nox 4 expression is increased in the mesangial cells of the kidneys. Insulin treatment reverses the increase.
Essentially, the Nox homologues are the final mediator in the cascade of oxidative damage whether the insult is hyperglycaemia, ischaemia or other AGEs. Better understanding of the central role Nox play in oxidative damage have triggered the development of inhibitors targeting the agonists or signalling intermediates that regulate the expression or function of Nox sub-units and subsequent ROS production as well as the downstream targets of Nox oxidases implicated in the pathological processes are being considered for the treatment of diabetic complications.
Among these inhibitors, the dual Nox4 and Nox1 inhibitors, referred as to GKT136901 and GKT137831, have drawn considerable attention. Pre-clinical studies performed with these inhibitors in experimental animal models indicate that they effectively attenuate the pathological changes observed in renal complication of type 1 and type 2 diabetes, atherosclerosis, ischaemic retinopathy, liver fibrosis and idiopathic pulmonary fibrosis.
See also Diabetes Nephropathy – time for a different strategy
Reference:
Yves Gorin*, and Fabien Wauquier. Upstream Regulators and Downstream Effectors of NADPH Oxidases as Novel Therapeutic Targets for Diabetic Kidney Disease. Mol. Cells 2015; 38(4): 285-296
Yves Gorin, Rita C. Cavaglieri, Khaled Khazim, et al. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes Am J Physiol Renal Physiol. 2015 Jun 1; 308(11)