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- Title
Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways.
- Authors
Jha, Jay C.; Dai, Aozhi; Garzarella, Jessica; Charlton, Amelia; Urner, Sofia; Østergaard, Jakob A.; Okabe, Jun; Holterman, Chet E.; Skene, Alison; Power, David A.; Ekinci, Elif I.; Coughlan, Melinda T.; Schmidt, Harald H.H.W.; Cooper, Mark E.; Touyz, Rhian M.; Kennedy, Chris R.; Jandeleit-Dahm, Karin
- Abstract
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.
- Subjects
INFLAMMATION; ANIMAL experimentation; DIABETES; FIBROSIS; REACTIVE oxygen species; DIABETIC nephropathies; MICE
- Publication
Diabetes, 2022, Vol 71, Issue 6, p1282
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db21-1079