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Abstract: FR-PO219

The Relative Roles of Nox4 vs. Nox5 in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Jha, Jay Chandra, Monash University, Melbourne, Victoria, Australia
  • Urner, Sofia, German Diabetes Center (DDZ), Düssedorf, Germany
  • Cooper, Mark E., Monash University, Melbourne, Victoria, Australia
  • Kennedy, Chris R., Kidney Research Centre, Ottawa, Ontario, Canada
  • Jandeleit-Dahm, Karin, Monash University, Melbourne, Australia
Background

Renal oxidative stress plays a crucial role in diabetic kidney disease (DKD). Recent studies have identified that Nox5 could be a main culprit in the context of human DKD. Nox5 is present in humans and rabbits but not in mice or rats. We examined the role of Nox4 vs. Nox5 in human DKD, in human renal cells as well as in rabbit and Nox5 transgenic (Tg) mouse model of DKD.

Methods

Expression of Nox5 was examined in human kidney biopsies. In vitro, Nox4 and Nox5 was silenced in human renal cells and were exposed to high glucose. In vivo, we have exposed the rabbits to high fat feeding (HF) as well as inducing insulin deficient diabetes using alloxan. We have generated a Nox5 knockout rabbit and a unique humanised Nox5 Tg mouse with concomitant Nox4 deletion.

Results

Expression of Nox5 was increased in kidney biopsies obtained from diabetic individuals. Nox5 shows the highest upregulation in response to high glucose in comparison to other Nox isoforms. Silencing of Nox5 reduces ROS formation and expression of proinflammatory and profibrotic cytokines and growth factors as well as putative elements that are implicated in DKD. Moreover, Nox5 is upstream of Nox4 and that Nox5 inhibition also downregulates Nox4, but not vice versa. HF and alloxan induced diabetic rabbits showed increased renal Nox5 expression in association with increased mesangial area and ECM accumulation along with upregulation of CTGF, fibronectin and MCP-1 as well as enhanced ROS production in the kidney. Expression of Nox5 in mesangial cells of Nox4KO diabetic mice demonstrated 30% increase in albuminuria, mesangial expansion, increased renal injury and inflammation via enhanced ROS production.

Conclusion

These findings suggest that Nox5 derived ROS accelerates renal injury in diabetes and provide proof of principle for the development of a new renoprotective agent in diabetes.