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Aquaporin 1 alleviates acute kidney injury via PI3K-mediated macrophage M2 polarization

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Abstract

Background

Lipopolysaccharide (LPS)-induced acute kidney injury (AKI) is associated with an abnormal immune response. Accumulating evidence has demonstrated that aquaporin 1 (AQP1) prevents kidney tissue injury in LPS-induced AKI by mediating immune response. However, the underlying mechanisms remain obscure. Macrophages as immune cells with multiple phenotypes are important mediators in tissue homeostasis and host defense. We propose that macrophage polarization is implicated in AQP1-mediated immune response.

Methods

Herein we established sepsis-induced AKI model rats through intraperitoneal injection of LPS into Wistar rats to reveal immune mechanism of damage. We also used LPS-induced mouse RAW264.7 cells to elucidate the molecular mechanism of macropage polarization.

Results

Histopathology showed that renal tubular epithelial cells in the model group were swollen, inflammatory exudation was obvious and the inflammatory factors, interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were increased. Western blotting showed PI3K was upregulated in the model group. Serum creatinine and urea nitrogen increased after LPS injection. Renal AQP1 mRNA is downregulated and serum AQP1 protein increased first and then decreased in LPS-induced AKI rats. M2 macrophage markers (Arg-1, CD206) were increased in repair stage. In addition, treatment of murine macrophages (RAW264.7) with AQP1 siRNA resulted in decreased PI3K activation and M2 polarization, but increased IL-6 and TNF-α. Moreover, inhibiting PI3K with wortmannin imitated the results of AQP1 silencing.

Conclusions

Macrophage M2 polarization is likely the cellular mechanism underlying the anti-AKI property of AQP1, and PI3K activation is involved in the AQP1-induced M2 phenotype switch.

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Acknowledgements

We thank Michal Bell, Ph.D., from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

This study was supported by the Natural Youth Science Foundation of China (grant no. 81501825) and Youth Science Foundation of Heilongjiang Province of China Grant (grant no. QC2012C035).

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Authors and Affiliations

  1. Department of Laboratory Diagnosis, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, People’s Republic of China

    ChunMei Liu, BoHui Li, KaiHong Tang, XueNing Dong, LongGe Xue, Guangming Su & Yingyu Jin

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  1. ChunMei Liu
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  2. BoHui Li
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Contributions

CL and BL performed the experiments. XD, LX, GS and KT analyzed the data. YJ made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, acquisition of funding. All authors gave their final approval of the version to be published.

Corresponding author

Correspondence to Yingyu Jin.

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Conflict of interest

The authors have no conflict of interest to disclose.

Ethics statement

The study protocol was approved by the Animal Care and Use Committee of Harbin Medical University (No: 2019014), and the experimental procedures were in accordance with the recommendations of the Guide for the care and use of Laboratory Animals, published by the US National Institutes of Health (NIH Publication no. 85-23. Revised 196).

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Liu, C., Li, B., Tang, K. et al. Aquaporin 1 alleviates acute kidney injury via PI3K-mediated macrophage M2 polarization. Inflamm. Res. 69, 509–521 (2020). https://doi.org/10.1007/s00011-020-01334-0

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