Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways

Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-alpha (PKC-alpha), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP). In preclinical models of DKD, overexpression of NOX5 in Nox4-deficient mice enhances kidney damage by increasing albuminuria and augmenting renal fibrosis and inflammation via enhanced ROS formation and the modulation of EGR1, TXNIP, ERK1/2, PKC-alpha, and PKC-epsilon. In addition, the only first-in-class NOX inhibitor, GKT137831, appears to be ineffective in the presence of NOX5 expression in diabetes. In vitro, silencing of NOX5 in human mesangial cells attenuated upregulation of EGR1, PKC-alpha, and TXNIP induced by high glucose levels, as well as markers of inflammation (TLR4 and MCP-1) and fibrosis (CTGF and collagens I and III) via reduction in ROS formation. Collectively, these findings identify NOX5 as a superior target in human DKD compared with other NOX isoforms such as NOX4, which may have been overinterpreted in previous rodent studies.

Automated summary

Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). This study demonstrates that NADPH oxidase 5 (NOX5) acts as a predominant pro-oxidant enzyme in DKD, independent of the previously characterized NOX4 pathway. The overexpression of NOX5 in DKD exacerbates kidney damage through enhanced ROS formation and modulation of key molecules involved in inflammation, fibrosis, and redox balance. Furthermore, the only available NOX inhibitor, GKT137831, is found to be ineffective in the presence of NOX5 expression in diabetes. These findings highlight the superior targeting potential of NOX5 as compared to other NOX isoforms like NOX4 in human DKD.