RENOPROTECTIVE EFFECT OF NOX5 INHIBITION IN DIABETIC KIDNEY DISEASE
Jay Jha1, Aozhi Dai1, Haritha RK1, Jaquet Vincent2, Mark E. Cooper1, Karin Jandeleit-Dahm1 1Department of Diabetes, Monash University, Melbourne, VIC, Australia2Universite de Geneve, Geneva, Switzerland
Abstract
Background and Aim:
Diabetic kidney disease (DKD) is the leading cause of end stage kidney failure. Pro-oxidant enzyme NADPH oxidase-NOX5 is considered as a major contributor of reactive oxygen species (ROS) and thereby aggravating renal injury in DKD. We aim to identify the pathogenic role of NOX5 and associated ROS-sensitive pathways in DKD using various experimental models including human kidney biopsies, human renal organoids and cells, humanised NOX5 transgenic mice and rabbit models as well as novel NOX5-specific inhibitors.
Methods: In vitro in diabetic environment, effect of NOX5 inhibition was assessed on ROS formation as well as on markers of fibrosis, inflammation and ROS-sensitive factors in human renal cell lines and in human kidney organoids. In vivo, we investigated the effect of NOX5 overexpression independent of NOX4 (an isoform previously characterised to be pathogenic in DKD) in streptozotocin (STZ) induced diabetic mice model.
Results: We identified increased expression of renal NOX5 in diabetic patients in association with upregulation of EGR-1 and down regulation of SULF-1. Silencing of Nox5 attenuated high glucose induced increased expression of markers of fibrosis and inflammation and restored the expression of endosulfatase, SULF-1, an enzyme responsible for maintaining integrity of glomerular filtration barrier . In vivo, overexpression of Nox5 independent of NOX4 pathways demonstrated an increase in albuminuria, renal fibrosis and inflammation in association with upregulation of EGR-1, ERK1/2, PKC-α, PKC-ε and TXNIP via enhanced ROS production in comparison to diabetic mice not expressing Nox5.
Conclusions: These findings suggest that NOX5 plays a key pathogenic dominant role in human DKD, thereby providing the fast track validation of NOX5 specific inhibitors to combat DKD in humans.
Biography
Dr. Jha is a previous JDRF and NHMRC funded early-mid career research fellow, who is already highly recognised in the field of diabetes and kidney disease particularly as it relates to oxidative stress. The leadership and significance of his research impact is reflected by translation of his preclinical work in DKD to clinical trials as well as by his highly cited publications (>2400 cites) in the leading journals of diabetes and nephrology. Dr. Jha has the skills and knowledge base with a strong track record in experimental diabetic complications protocols as well as expertise in molecular biology, renal phenotyping, data analysis and supervision of complex preclinical studies.
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