Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/28980
Title: Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-sensitive Pathways.
Austin 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
Affiliation: Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, 3004 Australia..
Institute for Clinical Diabetology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University, Dusseldorf, Germany..
Medicine (University of Melbourne)
Nephrology
Anatomical Pathology
Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark..
Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Canada..
Department of Pharmacology and Personalised Medicine, MeHNS, Faculty of Medicine, Health & Life Science, Maastricht University, Maastricht, the Netherlands..
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom..
Issue Date: 1-Jun-2022
Date: 2022
Publication information: Diabetes 2022; 71(6): 1282-1298
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/28980
DOI: 10.2337/db21-1079
ORCID: 0000-0002-8668-8592
0000-0003-3983-0581
0000-0003-2372-395X
Journal: Diabetes
PubMed URL: 35275988
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/35275988/
Type: Journal Article
Appears in Collections:Journal articles

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