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Kidney Week

Abstract: FR-PO376

Elucidating NOX5 as a Potential Therapeutic Target and a Biomarker of Kidney Disease in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 701 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
  • Ramanayaka Kankanamalage, Haritha Sandagiri Ramanayaka, Monash University Department of Diabetes, Melbourne, Victoria, Australia
  • Jaquet, Vincent, Universite de Geneve, Geneve, Genève, Switzerland
  • Cooper, Mark E., Monash University Department of Diabetes, Melbourne, Victoria, Australia
  • Jandeleit-Dahm, Karin, Monash University Department of Diabetes, Melbourne, Victoria, Australia
Background

Diabetes related chronic kidney disease (CKD) is the leading cause of end stage renal failure. Oxidative stress due to excessive production of reactive oxygen species plays a critical role in diabetic kidney disease (DKD). Pro-oxidant enzyme NADPH oxidase-NOX5 is considered as a major contributor of reactive oxygen species (ROS) mediated kidney damage in diabetes. We aim to identify the renoprotective effect of NOX5 inhibition in the in vitro setting of human derived renal cells and organoids exposed to diabetic milieu. We also aim to validate NOX5 as a biomarker for the early prediction of human DKD.

Methods

We examined the effect of NOX5 silencing or inhibition by NOX5-specific inhibitors on ROS formation along with markers of fibrosis, inflammation and ROS-sensitive factors in human renal cells and iPSC derived renal organoids. We assessed the expression of NOX5 in human kidney biopsies as well as in urine and serum obtained from non-diabetic and diabetic individuals by ELISA and FACS. Correlation between NOX5 level and clinical data sets including albuminuria was performed.

Results

Renal NOX5 expression was increased in diabetic patients in comparision to non-diabetic subjects. Increased expression of NOX5 was associated with upregulation of a transcription factor, EGR-1 and down regulation of an endosulfatase, SULF-1 (an enzyme which maintains the integrity of glomerular filtration barrier) in diabetes. Both genetic silencing of NOX5 in renal cells and pharmacological inhibition of NOX5 in renal cells as well as in renal organoids attenuated high glucose induced upregulation of CTGF, MCP-1, TLR-4 and EGR-1 and restored the expression of SULF-1 via reduction in ROS formation. These novel findings suggest the role for NOX5 in renal fibrosis and inflammation as well as in the regulation of EGR-1 and SULF-1 in diabetes like conditions. Moreover, increased level of NOX5 in human urine and serum was observed in diabetic individuals even in the absence of albuminuria.

Conclusion

These findings suggest that NOX5 plays a key role in human DKD by promoting inflammation and fibrosis, thereby providing the fast track validation of NOX5 specific inhibitors to combat DKD in humans. In addition, NOX5 appears to be a potential biomarker for the early detection of DKD.