PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation
- Anhui Medical University, China
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file.
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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.
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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PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation
eLife 13:e89740.
https://doi.org/10.7554/eLife.89740
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