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Abstract: TH-PO201

Xanthine Oxidase Inhibition Ameliorates High Glucose-Induced Oxidative Stress by Activating AMPK Through the Purine Salvage Pathway in Glomerular Endothelial Cells

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hong, Yu Ah, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Yang, Keum-Jin, Catholic University of Korea Daejeon St Mary's Hospital, Daejeon, Korea (the Republic of)
  • Choi, Wonjung, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Chang, Yoon-Kyung, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Suk young, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, Catholic University of Korea School of Medicine, Seoul, Korea (the Republic of)
Background

Oxidative stress plays a crucial role in the pathogenesis of diabetic kidney disease. Xanthine oxidase (XO) contribute to reactive oxygen species (ROS) production, and XO inhibitors have been reported to the protection of kidney diseases. We investigated the cytoprotective mechanism associated with activated AMP-activated protein kinase (AMPK) by XO inhibition in high glucose (HG) condition.

Methods

Glomerular endothelial cells (GEnCs) exposed to HG were treated with or without febuxostat for 48 hours, and then the phosphorylation of AMPK and its related signaling pathway were evaluated.

Results

Febuxostat enhanced cell survival in a dose-dependent manner and decreased ROS in HG-treated GEnCs. Febuxostat enhanced phosphorylation of AMPK, and activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α, and dephosphorylation of the Forkhead box O (FoxO)3a in HG-treated GEnCs. Febuxostat also suppressed NADPH oxidase expressions and enhanced SOD activity in HG-treated GEnCs. The expressions of xanthine/hypoxanthine were significantly reduced, and the levels of xanthine oxidoreductase were increased in HG-treated GEnCs, and these findings were attenuated by febuxostat. The intracellular AMP/ATP ratio was inhibited in HG-treated GEnCs and enhanced by febuxostat. AMPK inhibition using small interfering RNA suppressed HPRT1 activity and suppressed PGC-1α-FoxO3a signaling and finally abolished the antioxidant effects by febuxostat in HG-treated GEnCs.

Conclusion

XO inhibition attenuates HG-induced oxidative stress through the activation of AMPK–PGC-1α–FoxO3a-NADPH oxidase signaling via purine salvage pathway.

Funding

  • Government Support – Non-U.S.