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Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression

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Abstract

Background

Endoplasmic reticulum (ER) stress has been implicated in the development of various renal diseases. Thus, inhibition of ER stress using pharmacological agents may serve as a promising therapeutic approach. We postulated that febuxostat, a novel xanthine oxidase inhibitor, could suppress the ER stress through upregulation of SIRT1 (silent mating type information regulation 2 homolog 1)-AMPK (AMP activated protein kinase)-HO-1 (heme oxygenase-1)/thioredoxin expression.

Methods

We examined the effect of febuxostat on the ER stress induced by a chemical inducer, tunicamycin and non-chemical agents such as angiotensin II, aldosterone, high glucose, and albumin in renal tubular cells. We further examined the in vivo effects of febuxostat using mouse model of kidney disease induced by unilateral ureteral obstruction (UUO). Expression of ER stress was measured by western blot analysis and immunohistochemical stain.

Results

Febuxostat suppressed the ER stress induced by tunicamycin and non-chemical agents, as shown by inhibition of increased GRP78 (glucose-related protein78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor 2α) expression. Inhibitory effect of febuxostat was mediated through upregulation of SIRT1-AMPK followed by induction of HO-1 and thioredoxin. In animal model of UUO, febuxostat reduced the UUO-induced ER stress, which was abolished by pretreatment with SIRT1 inhibitor (sirtinol) and AMPK inhibitor (compound C).

Conclusion

Febuxostat could suppress the ER stress caused by various ER stress inducers through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Targeting these pathways might serve as one of the possible therapeutic approaches in kidney diseases under excessive ER stress.

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Acknowledgements

Reprints request to Sang Koo Lee M.D., Division of Nephrology, Department of Internal Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: sklee2@amc.seoul.kr.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Hyosang Kim, Chung Hee Baek, Jai Won Chang, Won Seok Yang & Sang Koo Lee

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  1. Hyosang Kim
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  2. Chung Hee Baek
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  3. Jai Won Chang
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Correspondence to Sang Koo Lee.

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All the authors have declared no competing interest.

Ethical approval

All procedures performed in animal experiments were approved by Institutional Animal Care and Use Committee of Asan Institute for Life Sciences (Subject No: 2017-13-039).

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Kim, H., Baek, C.H., Chang, J.W. et al. Febuxostat, a novel inhibitor of xanthine oxidase, reduces ER stress through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Clin Exp Nephrol 24, 205–215 (2020). https://doi.org/10.1007/s10157-019-01804-8

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  • DOI: https://doi.org/10.1007/s10157-019-01804-8

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