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Abstract: SA-PO254

Characterising the Pro-Oxidant Enzyme NOX5 as a Potential Therapeutic Target for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Jha, Jay Chandra, Monash University Department of Diabetes, Melbourne, Victoria, Australia
  • Dai, Aozhi, Monash University Department of Diabetes, Melbourne, Victoria, Australia
  • Jaquet, Vincent, Universite de Geneve, Geneva, Geneva, Switzerland
  • Cooper, Mark E., Monash University Department of Diabetes, Melbourne, Victoria, Australia
  • Jandeleit-Dahm, Karin, Monash University Department of Diabetes, Melbourne, Victoria, Australia

Group or Team Name

  • Diabetic Kidney Disease Lab.
Background

Diabetic kidney disease (DKD) is the leading cause of end stage renal failure. Enhanced level of renal reactive oxygen species (ROS) produced by the pro-oxidant enzyme NADPH oxidase- NOX5 is considered a major contributor in aggravating renal injury in DKD. We aim to characterise the pathogenic role of NOX5 and associated ROS-sensitive pathways in DKD using various experimental models including human diabetic kidney biopsies, human diabetic renal organoids and cells as well as humanised NOX5 transgenic diabetic mice models.

Methods

We examined the expression of NOX5 in association with ROS-sensitive factors including a transcription factor, EGR1 (early growth response 1), a protein kinase, PKC-α and a key metabolic gene involved in redox balance, TXNIP (thioredoxin-interacting protein), as well as ROS production in human kidney biopsies as well as in human renal organoids and cells. We assessed the effect of NOX5 inhibition using genetic manipulation and pharmacological inhibition approaches in human renal cells and organoids exposed to diabetic milieu environment. In vivo, we also assessed the effect of Nox5 overexpression independent of NOX4 in humanised Nox5 transgenic mice in the presence or absence of diabetes.

Results

We identified increased expression of renal NOX5 in diabetic patients in association with upregulation of EGR-1, PKC-α and TXNIP. Silencing of Nox5 attenuated high glucose induced gene expression of markers of fibrosis and inflammation as well as downregulation of EGR-1, PKC-α and TXNIP. Our data also suggest that Nox5 appears to be upstream of Nox4 and that Nox5 inhibition also downregulates Nox4, but not vice versa. 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.

Conclusion

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.