Investigating novel therapeutic targets and biomarkers of chronic kidney disease in diabetes

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 diabetic nephropathy, 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 unknown. This project will mainly focus on the role of Nox5 in the development and progression of diabetic nephropathy. The projects will utilize novel NOX5 specific inhibitors in various kidney disease models including stem cells derived human kidney organoids and a unique humanised Nox5 knockin mouse, where Nox5 is expressed only in the key renal cells implicated in diabetic kidney disease as well rabbit models of diabetes and kidney disease. The experimental end point will be to assess the 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 renal complication of diabetes. In addition, the project will also identify novel biomarkers of kidney disease including NOX5 using human blood and urine samples. 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.