The role of pro-oxidant enzyme NOX5 in diabetes associated complications

The development of diabetic complications including vascular and renal disease is enhanced in diabetic patients. However, the underlying mechanism as to why this disease process is accelerated is largely unknown. Oxidative stress has been proposed to play a key role in the development of diabetic complications including vascular and renal in, particularly the NADPH oxidase (Nox) family. There are primarily 4 Nox isoforms that have been shown to be important in the development of diabetic complications, Nox1, 2, 4 and 5. All of these isoforms have increased expression and activity in diabetic patients. Our group has established a role for the Nox1 isoform in the development of diabetic atherosclerosis, and the Nox4 isoform in diabetic kidney disease. However, to date a role for the Nox5 isoform in diabetic complications is poorly understood. This project will mainly focus on the role of Nox5 in the development and progression of diabetic complications including atherosclerosis and nephropathy. The projects will utilize a unique Nox5 KO rabbit and highly novel humanised Nox5 knockin mouse, where Nox5 is expressed only in the vascular smooth muscle cells or the endothelial cells. The experimental end point will be to assess the vascular injury, renal function, albuminuria, renal structural injuries (glomerulosclerosis and tubulointerstitial fibrosis) as well as markers of fibrosis and inflammation. The project will involve applying various experimental techniques that include immunohistochemistry, RT-PCR and western blot for gene and protein expression analysis and cell culture analysis to delineate the role that Nox5 plays in the development of diabetic complications. References 1. Jay C Jha et al., NADPH oxidase-Nox5 accelerates renal injury in diabetic nephropathy. Diabetes; 66 (10):2691-2703; 2017. 2. Jha, J.C., et al., Podocyte-specific Nox4-NADPH oxidase deletion affords renoprotection in diabetic nephropathy. Diabetologia, 2015. 3. Jha, J.C., et al., Genetic Targeting or Pharmacological Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy. J Am Soc Nephrol, 2014. 4. Jha, J. C., et al., Diabetes and Kidney Disease: Role of Oxidative Stress. Antioxid Redox Signal, 2016. 5. Gray SP., et al. Nox1 plays a key role in diabetes associated atherosclerosis. Circulation, 2013.