Excessive generation of renal reactive oxygen species (ROS) contributes significantly to diabetic kidney damage (DKD). For a study, researchers provided crucial data indicating that the pro-oxidant enzyme NADPH oxidase 5 (NOX5) had a prominent pathogenic role in DKD, irrespective of the previously identified NOX4 pathway. They discovered the increased expression of renal NOX5 in diabetic patients, which was associated with increased ROS formation and upregulation of ROS-sensitive factors such as early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and thioredoxin-interacting protein, a key metabolic gene involved in redox balance (TXNIP).
Overexpression of NOX5 in Nox4-deficient animals increased kidney damage by increasing albuminuria and boosting renal fibrosis and inflammation through increased ROS production and regulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. Overexpression of NOX5 in Nox4-deficient animals increases kidney damage by increasing albuminuria and boosting renal fibrosis and inflammation via increased ROS production and regulation of EGR1, TXNIP, ERK1/2, PKC-α, and PKC-ε. Furthermore, GKT137831, the sole first-in-class NOX inhibitor, appears inefficient in the presence of NOX5 expression in diabetes. In human mesangial cells, silencing NOX5 reduced the elevation of EGR1, PKC-α, and TXNIP triggered by high glucose levels, as well as indicators of inflammation (TLR4 & MCP-1) and fibrosis (CTGF and collagens I and III) via ROS production. The findings showed that NOX5 was a better target in human DKD than other NOX isoforms like NOX4.
