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Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis

  • Authors:
    • Huimin Zhang
    • Fangfang Lai
    • Xi Cheng
    • Yu Wang
  • View Affiliations / Copyright

    Affiliations: Renal Division, Department of Medicine, Peking University First Hospital, Beijing 100034, P.R. China, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China, Institute of Nephrology, Peking University, Beijing 100034, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 161
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    Published online on: July 6, 2023
       https://doi.org/10.3892/mmr.2023.13048
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Abstract

The Na/K‑ATPase/Src complex is reportedly able to affect reactive oxygen species (ROS) amplification. However, it has remained elusive whether NADPH oxidases (NOXs) are involved in this oxidant amplification loop in renal fibrosis. To test this hypothesis, interactions between oxidative features and Na/K‑ATPase/Src activation were examined in a mouse model of unilateral urethral obstruction (UUO)‑induced experimental renal fibrosis. Both 1‑tert‑butyl‑3‑(4‑chlorophenyl)‑1H‑pyrazolo[3,4‑d]pyrimidin‑4‑amine (PP2) and apocynin significantly attenuated the development of UUO‑induced renal fibrosis. Apocynin administration attenuated the expression of NOXs and oxidative markers (e.g., nuclear factor erythroid 2‑related factor 2, heme oxygenase‑1,4‑hydroxynonenal and 3‑nitrotyrosine); it also partially restored Na/K‑ATPase expression and inhibited the activation of the Src/ERK cascade. Furthermore, administration of PP2 after UUO induction partially reversed the upregulation of NOX2, NOX4 and oxidative markers, while inhibiting the activation of the Src/ERK cascade. Complementary experiments in LLC‑PK1 cells corroborated the in vivo observations. Inhibition of NOX2 by RNA interference attenuated ouabain‑induced oxidative stress, ERK activation and E‑cadherin downregulation. Thus, it is indicated that NOXs are major contributors to ROS production in the Na/K‑ATPase/Src/ROS oxidative amplification loop, which is involved in renal fibrosis. The disruption of this vicious feed‑forward loop between NOXs/ROS and redox‑regulated Na/K‑ATPase/Src may have therapeutic applicability for renal fibrosis disorders.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang H, Lai F, Cheng X and Wang Y: Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis. Mol Med Rep 28: 161, 2023.
APA
Zhang, H., Lai, F., Cheng, X., & Wang, Y. (2023). Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis. Molecular Medicine Reports, 28, 161. https://doi.org/10.3892/mmr.2023.13048
MLA
Zhang, H., Lai, F., Cheng, X., Wang, Y."Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis". Molecular Medicine Reports 28.3 (2023): 161.
Chicago
Zhang, H., Lai, F., Cheng, X., Wang, Y."Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis". Molecular Medicine Reports 28, no. 3 (2023): 161. https://doi.org/10.3892/mmr.2023.13048
Copy and paste a formatted citation
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Spandidos Publications style
Zhang H, Lai F, Cheng X and Wang Y: Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis. Mol Med Rep 28: 161, 2023.
APA
Zhang, H., Lai, F., Cheng, X., & Wang, Y. (2023). Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis. Molecular Medicine Reports, 28, 161. https://doi.org/10.3892/mmr.2023.13048
MLA
Zhang, H., Lai, F., Cheng, X., Wang, Y."Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis". Molecular Medicine Reports 28.3 (2023): 161.
Chicago
Zhang, H., Lai, F., Cheng, X., Wang, Y."Involvement of NADPH oxidases in the Na/K‑ATPase/Src/ROS oxidant amplification loop in renal fibrosis". Molecular Medicine Reports 28, no. 3 (2023): 161. https://doi.org/10.3892/mmr.2023.13048
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