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Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-sensitive Pathways
figureposted on 2022-03-14, 22:48 authored by 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. Schmidt, Mark E. Cooper, Rhian M Touyz, Chris R. Kennedy, Karin Jandeleit-Dahm
Excessive production of renal reactive oxygen species (ROS) play a major role in diabetic kidney disease (DKD). Here, we provide key novel findings demonstrating the predominant pathological role of the prooxidant enzyme NADPH oxidase-NOX5 in DKD, independent of the previously characterised NOX4 pathway. In diabetic patients, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors EGR-1 (early growth response 1), PKC-α (protein kinase C- α) and a key metabolic gene involved in redox balance, TXNIP (thioredoxin-interacting protein). 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 high glucose induced upregulation of EGR1, PKC-α, and TXNIP 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 to other NOX isoforms such as NOX4 which may have been overinterpreted in previous rodent studies.
This work was supported by the National Health & Medical Research Council of Australia (NHMRC) project grant (APP100585) as well as by the Juvenile Diabetes Research Foundation (JDRFF) grants (2-SRA 2014-259-Q-R). KJD and MEC received Senior Research Fellowships from the Australian NHMRC (APP1059124 and APP1078808) and JCJ received Early Career Research Fellowships from Australian NHMRC (APP1126169) and JDRF (201302918).