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Abstract: SA-PO232

Inhibition of Xanthine Oxidase Protects Diabetic Nephropathy Through Amelioration of Oxidative Stress via VEGF-NOX-FoxO3a Signaling Pathway

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

Xanthine oxidase (XO) is one of major source of reactive oxygen species, and a XO inhibitor, febuxostat has been reported to the protection of kidney diseases. We investigated whether febuxostat exerts renoprotective effects against diabetic kidney disease (DKD).

Methods

Febuxostat (5 mg/kg) was administrated to 8-week Male C57BL/6 mice via intraperitoneal route for 8 weeks in streptozotocin (STZ)-treated diabetic mice. We also evaluated the antioxidant effects of febuxostat and its mechanism using high glucose (HG)-treated cultured human glomerular endothelial cells (HGECs).

Results

Serum cystatin C, albuminuria and mesangial matrix expansion were significantly decreased in febuxostat-treated diabetic mice. Febuxostat also reduced serum uric acid, kidney XO and xanthine dehydrogenase levels in diabetic mice. Febuxostat suppressed the expression of vascular endothelial growth factor (VEGF) mRNA, VEGF receptor (VEGFR)1 and 3, NADPH oxidase (NOX)1, 2, and 4, and the levels of their catalytic subunit mRNA in diabetic mice. Febuxostat was accompanied by the downregulation of Akt phosphorylation, followed by the suppression of transcription factor forkhead box O3a (FoxO3a) phosphorylation and the enhancement of endothelial nitric oxide synthase (eNOS). In addition, the blockade of VEGFR1 or VEGFR3 abolished the antioxidant effects of febuxostat via NOXs-FoxO3a-eNOS signaling in HG-treated cultured HGECs. Finally, febuxostat improved oxidative stress in both in vivo and in vitro models of DKD.

Conclusion

The inhibition of XO by febuxostat was associated with the inhibition of VEGF, which consequently ameliorated oxidative stress related to NOXs-FoxO3a-eNOS signaling in DKD.

Funding

  • Government Support – Non-U.S.