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Download fileIndependent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-sensitive Pathways
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posted 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-DahmExcessive 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.