Project Summary/Abstract Glomerular epithelial cell/podocyte injury is a prominent pathological feature of diabetic nephropathy (DN). In podocytes, hyperglycemia causes alteration of slit diaphragm proteins, foot process effacement, apoptosis and cell detachment, events that ultimately results in loss of renal function. High glucose concentrations (HG) and oxidative stress are potential mediators of glomerular injury in diabetes. We have evidence that Dual oxidase 2 (Duox2) is expressed in glomerular cells and contributes to HG-induced reactive oxygen species (ROS) generation as well as podocyte injury. Additionally, we have demonstrated that glomeruli isolated from DuoxA-/- mice were protected from high glucose-induced hydrogen peroxide generation. The central hypothesis of this proposal is that the ROS generated by Duox2 play a pivotal role in glomerular lesions and podocyte injury in the diabetic kidney. The goals of this proposal are to utilize in vitro and in vivo approaches to establish the importance of Duox2 in podocyte injury in the diabetic environment and identify the factors that are modulating Duox2 activity/expression. The role of Duox activators (DuoxA), translational mechanisms, and calcium in Duox2 activation will be explored. For the in vivo studies, we will utilize previously collected kidney cortices from diabetic and non-diabetic mice where DuoxA function is impaired. As no data related to Duox enzyme expression and function within podocytes are available, the experiments proposed should serve as proof of concept to demonstrate the utility of targeting the Duox/DuoxA system to reduce diabetes-mediated glomerular lesions. Characterization of the deleterious actions of Duox2 and identification of its regulators will contribute to the design of novel therapeutic interventions and will help establish adjunct therapy to treat DN. The studies will stress the relevance of the development of modulators of Duox2 expression and activity in the kidney as therapeutic agents to prevent or reverse DN. Furthermore, this proposal will enhance the research and educational infrastructure at the University of the Incarnate Word, introducing biomedical research experiences to underrepresented minority students who would otherwise lack such opportunities.

Project Narrative: Public Health Relevance Statement Diabetes and diabetic nephropathy (DN) are major causes of morbidity in the general population. There is an urgent medical need for identification of novel targets in the development of strategies for rational treatment of DN. Our objective is to characterize the role of Duox2 in DN and identify it as a convenient target for therapeutic intervention as identifying specific sources of oxidants will allow targeted therapy to prevent DN and could translate to treating patients with specific antioxidant therapy.