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

• DOI: 10.2337/db21-1079
• Publication Date: 2022-03-11T21:48:57Z
• Authors: Jay C. Jha; Aozhi Dai; Jessica Garzarella; Amelia Charlton; Sofia Urner; Jakob A. Østergaard; Jun Okabe; Chet E. Holterman; Alison Skene; David A. Power; Elif I. Ekinci; Melinda T. Coughlan; Harald H.H.W. Sch...; Mark E. Cooper; Rhian M. Touyz; Chris R. Kennedy; Karin Jandeleit-Dahm
• Keywords: Inflammation; 0301 basic medicine; 0303 health sciences; NADPH Oxidases; Fibrosis; Mice; 03 medical and health sciences; NADPH Oxidase 5; NADPH Oxidase 4; Diabetes Mellitus; Animals; Humans; Diabetic Nephropathies; Reactive Oxygen Species

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-α (PKC-α), 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-α, and PKC-ε. 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-α, 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.