PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation

Abstract

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively, but the mechanism underlying AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, inflammatory factor, and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of Pstpip2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. Conversely, restoring normal Pstpip2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-κB pathway and induced NET formation via the IL-20Rβ receptor. Concurrently, NETs promoted apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-κB pathway activation in RTECs, inhibiting RTEC apoptosis, and reducing kidney damage. Our findings indicated that neutrophils and NETs play a key role in AAN and therapeutic targeting of PSTPIP2/NF-κB/IL-19/IL-20Rβ might extend novel strategies to minimize Aristolochic acid I-mediated acute kidney injury and apoptosis.

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All data generated or analyzed during this study are included in the manuscript and supporting file.

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Author details

  1. Changlin Du

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Chuanting Xu

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Pengcheng Jia

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Na Cai

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Zhenming Zhang

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Wenna Meng

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Lu Chen

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Zhongnan Zhou

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Qi Wang

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Rui Feng

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Jun Li

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Xiaoming Meng

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Cheng Huang

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    For correspondence
    huangcheng@ahmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  14. Taotao Ma

    Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
    For correspondence
    mataotao@ahmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2208-2505

Funding

Department of Science and Technology of Anhui Province (Natural Science Foundation of Anhui Province(2008085MH273))

  • Taotao Ma

Department of Science and Technology of Anhui Province (Anhui Fund for Distinguished Young Scholars(2022AH020050))

  • Taotao Ma

Anhui Medical University (Research Fund of Anhui Institute of translational medicine(2022zhyx-B07))

  • Taotao Ma

Anhui Medical University (Research Fund of Anhui Institute of translational medicine(2021zhyx-B06))

  • Cheng Huang

Anhui Medical University (Scientific Research Promotion Fund of Anhui Medical University (2022xkjT010))

  • Cheng Huang

Anhui Medical University (Scientific Research Platform Improvement Project of Anhui Medical University (2023xkjT049))

  • Jun Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed in accordance with the Regulations of the Experimental Animal Administration issued by the State Committee of Science and Technology of China. Efforts were made to minimize the number of animals used and their suffering. Animals were maintained in accordance with the guidance of the Center for Developmental Biology, Anhui Medical University, for the care and use of laboratory animals, and all experiments used protocols approved by the institutions' subcommittees on animal care. (approval No. LLSC20190682).

Human subjects: This study was approved by the Biomedical Ethics Committee of the Anhui Medical University (ethical clearance no.: 83230373). The experiments were conducted with the understanding and written consent of each patient.

Reviewing Editor

  1. Ilse S Daehn, Icahn School of Medicine at Mount Sinai, United States

Version history

  1. Received: May 29, 2023
  2. Accepted: February 4, 2024
  3. Accepted Manuscript published: February 5, 2024 (version 1)

Copyright

© 2024, Du et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Changlin Du
  2. Chuanting Xu
  3. Pengcheng Jia
  4. Na Cai
  5. Zhenming Zhang
  6. Wenna Meng
  7. Lu Chen
  8. Zhongnan Zhou
  9. Qi Wang
  10. Rui Feng
  11. Jun Li
  12. Xiaoming Meng
  13. Cheng Huang
  14. Taotao Ma
(2024)
PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation
eLife 13:e89740.
https://doi.org/10.7554/eLife.89740

Share this article

https://doi.org/10.7554/eLife.89740

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