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Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway

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Abstract

Renal interstitial fibrosis is a major pathologic feature of diabetic nephropathy, while the pathogenesis and therapeutic interventions of diabetic renal interstitial fibrosis are not well established. In this study, we first demonstrated that high glucose could induce renal fibroblast (NRK-49F) cell proliferation and activation to myofibroblasts, accompanied by a significant increase in the intracellular levels of reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). ROS-mediated ERK1/2 activation was found to play a crucial role in high glucose-induced fibroblast proliferation and activation. Resveratrol, like the NOX4-targeting small interfering RNA (siRNA), markedly inhibited high glucose-induced fibroblast proliferation and activation by reducing NOX4-derived ROS production. It was then revealed that the increase in the expression of NOX4 induced by high glucose was due to the inactivation of AMP-activated protein kinase (AMPK), which could be reversed by resveratrol. Further in vivo investigation demonstrated that resveratrol treatment significantly attenuated renal fibrosis in db/db mice, accompanied by an evident increase in phospho-AMPK and decrease in NOX4. In summary, our results suggest that high glucose can directly promote renal fibroblasts proliferation and activation in a ROS-dependent manner, and resveratrol is a potential therapeutic agent against diabetic renal fibrosis via regulation of AMPK/NOX4/ROS signaling.

Key message

  • Resveratrol inhibits high glucose-induced NRK cell activation by decreasing NOX4-derived ROS.

  • Resveratrol inhibits high glucose-induced NOX4 expression in NRK cells via activation of AMPK.

  • ROS-activated ERK1/2 signaling is involved in high glucose-induced NRK cell activation.

  • Resveratrol attenuated renal fibrosis in db/db mice via regulation of AMPK/NOX4/ROS signaling.

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Acknowledgments

This study was supported by research grants from the National Natural Science Foundation of China (nos. 81270290, 81500561, and 81500567) and the project for overseas student from Ministry of Human Resources and Social Security of the People’s Republic of China.

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    Authors and Affiliations

    1. Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People’s Republic of China

      Ting He, Jiachuan Xiong, Ling Nie, Yanlin Yu, Xu Guan, Xinli Xu, Tangli Xiao, Ke Yang, Liang Liu, Daohai Zhang, Yunjian Huang, Jingbo Zhang & Jinghong Zhao

    2. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Third Military Medical University, Chongqing, 400038, People’s Republic of China

      Junping Wang

    3. Center for Renal Translational Medicine, Division of Nephrology-Hypertension, University of California, La Jolla, CA, USA

      Kumar Sharma

    4. Veterans Administration San Diego HealthCare System, La Jolla, CA, USA

      Kumar Sharma

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    1. Ting He
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    Correspondence to Jinghong Zhao.

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    Ting He and Jiachuan Xiong contributed equally to this work.

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    He, T., Xiong, J., Nie, L. et al. Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway. J Mol Med 94, 1359–1371 (2016). https://doi.org/10.1007/s00109-016-1451-y

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    • DOI: https://doi.org/10.1007/s00109-016-1451-y

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