NOX, NOX, Are You Here? The Emerging Role of NOX5 in Diabetic Neuropathy

Diabetic neuropathy (DN) is one of the most common complications of diabetes worldwide, affecting up to 60% of all diabetic patients. Although the pathogenesis of DN is poorly understood, it is widely accepted that reactive oxygen species (ROS) mediate in part the cellular and molecular injury observed in DN. NADPH oxidase (Nox) enzymes generate ROS and of the 7 isoforms, NOX5 is present only in man. In this study, we aimed to investigate a role for NOX5 in DN by identifying the cellular localization, methylation status and expression levels of NOX5 in cutaneous nerve fibers and sural nerve biopsies of diabetic patients. Cellular localization of NOX5, myelin basic protein (MBP) and protein gene product (PGP) 9.5 were determined in cutaneous nerve fibers of controls and subjects with DN. NOX5 methylation status and protein levels were assessed in subjects with DN that were divided into two groups based on changes in sural nerve myelinated fiber density: regenerators (showing significant nerve regeneration) and degenerators (showing significant nerve degeneration). NOX5 expression was present in deep myelinated cutaneous fibers. Bisulfite sequencing revealed that the NOX5 promoter, enriched with CpG sites, is hypomethylated in sural nerve biopsies of the degenerator cohort compared to the regenerator. The increase in NOX5 expression in degenerator sural nerves was accompanied with a decrease in MBP levels relative to the regenerator group. Our results highlight that in subjects with DN with sural nerve degeneration, there is hypomethylation of the NOX5 promoter associated with an increase in its protein expression, suggesting a potential epigenetic and mechanistic role of NOX5 in DN.