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Hydroxychloroquine suppresses anti-GBM nephritis via inhibition of JNK/p38 MAPK signaling

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Abstract

Background

Anti-glomerular basement membrane (anti-GBM) nephritis, characterized by glomerular crescent formation, requires early treatment because of poor prognosis. Hydroxychloroquine (HCQ) is an antimalarial drug with known immunomodulatory, anti-inflammatory, and autophagy inhibitory effects; it is recognized in the treatment of autoimmune diseases such as systemic lupus erythematosus. However, its effect on anti-GBM nephritis remains unknown. In this study, we investigated the effect of HCQ on anti-GBM nephritis in rats.

Methods

Seven-weeks-old male WKY rats were administered anti-GBM serum to induce anti-GBM nephritis. Either HCQ or vehicle control was administered from day 0 to day 7 after the induction of nephritis. Renal function was assessed by measuring serum creatinine, proteinuria, and hematuria. Renal histological changes were assessed by PAS staining and Masson trichrome staining, and infiltration of macrophages was assessed by ED-1 staining. Mitogen-activated protein kinase (MAPK) was evaluated by western blotting, while chemokine and inflammatory cytokines were evaluated by enzyme-linked immunosorbent assay using urine sample.

Results

HCQ treatment suppressed the decline in renal function. Histologically, extracapillary and intracapillary proliferations were observed from day 1, while fibrinoid necrosis and ED-1 positive cells were observed from day 3. Rats with anti-GBM nephritis showed high levels of monocyte chemotactic protein-1 and tumor necrosis factor-α. These changes were significantly suppressed following HCQ treatment. In addition, HCQ suppressed JNK/p38 MAPK phosphorylation.

Conclusion

HCQ attenuates anti-GBM nephritis by exerting its anti-inflammatory effects via the inhibition of JNK/p38 MAPK activation, indicating its therapeutic potential against anti-GBM nephritis.

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Acknowledgements

We thank Ms. Ryoko Yamamoto for her excellent experimental assistance.

Funding

This research received no specific grants from any funding agency.

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Authors and Affiliations

  1. Department of Nephrology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Miki Torigoe, Yoko Obata, Hiro Inoue, Kenta Torigoe & Tomoya Nishino

  2. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Akira Kinoshita

  3. Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Takehiko Koji

  4. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Hiroshi Mukae

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  1. Miki Torigoe
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  4. Kenta Torigoe
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Correspondence to Yoko Obata.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Approval number 1506261242-8).

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Torigoe, M., Obata, Y., Inoue, H. et al. Hydroxychloroquine suppresses anti-GBM nephritis via inhibition of JNK/p38 MAPK signaling. Clin Exp Nephrol 27, 110–121 (2023). https://doi.org/10.1007/s10157-022-02285-y

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  • DOI: https://doi.org/10.1007/s10157-022-02285-y

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