Role of NADPH Oxidase 5 (NOX5) in Diabetic Neuropathy
Eva Feldman   (Ann Arbor, MI)
Peripheral neuropathy (PN) is a common complication of diabetes, prediabetes, and obesity. There is no effective treatment for PN, and approaches that slow or reverse disease progression are urgently needed. Although the pathogenesis of PN is poorly understood, evidence has shown that reactive oxygen species (ROS) mediate in part the cellular and molecular injury observed in PN. NADPH oxidase (NOX) enzymes generate ROS, and we are interested in the role of NOX5, one of the 7 NOX isoforms, in PN. NOX5 is present only in man and absent in rats and mice, and our preliminary results demonstrate that the NOX5 gene is regulated by hypomethylation in peripheral nerves of diabetic subjects with PN, and that this hypomethylation promotes increased NOX5 gene and protein expression and enhanced ROS generation. Our objective in this proposal is to extend these observations to validate the role of NOX5 as a major player in the development and progression of PN. We hypothesize that NOX5 upregulation contributes to the development of PN. To test this hypothesis, we will: 1) generate and characterize a transgenic (Tg) mouse model expressing human NOX5 specifically in Schwann cells and evaluate the effects of NOX5 expression on PN progression in the setting of type 2 diabetes (T2D), and 2) determine the therapeutic efficacy of NOX5 inhibition using a specific NOX inhibitor (GKT137831; Cayman Chemical, Michigan) on PN in our Tg mouse model with T2D. These studies will provide insight into the therapeutic potential of a new mechanism-based approach and thereby support our long-term goal of identifying therapeutic targets that restore nerve function in prediabetic, diabetic, and obese subjects with PN.
Data for this report has not yet been released.