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Chloroquine attenuates TLR3-mediated plasminogen activator inhibitor-1 expression in cultured human glomerular endothelial cells

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Abstract

Background

Chloroquine, an antimalarial agent, has been reported to prevent the risk of thrombosis and decrease renal damage in patients with systemic lupus erythematosus (SLE); however, its detailed mechanisms remain unclear. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis and is involved in fibrin deposition in glomeruli. Since upregulation of glomerular Toll-like receptor 3 (TLR3) signaling reportedly plays a pivotal role in the pathogenesis of lupus nephritis (LN), we examined whether chloroquine affects TLR3-mediated expression of PAI-1 in cultured human glomerular endothelial cells (GECs).

Methods

We examined the effect of polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, on PAI-1 and tissue plasminogen activator (t-PA) expression in GECs. Then, we analyzed whether pretreatment of chloroquine or dexamethasone inhibits poly IC-induced expression of these proteins using reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay.

Results

Poly IC increased PAI-1 expression in a time- and concentration-dependent manner, but did not affect t-PA expression in GECs. RNA interference against TLR3 inhibited poly IC-induced PAI-1 expression. Interestingly, pretreating cells with chloroquine, and also hydroxychloroquine, but not dexamethasone, attenuated poly IC-induced PAI-1 expression in GECs.

Conclusion

Considering that TLR3 signaling is implicated in LN pathogenesis, our results suggest that chloroquine exert postulated renoprotective effects by inhibiting PAI-1 expression.

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Acknowledgements

This study was supported by Grants-in-Aid of the Japan Society for Promotion of Science (JSPS KAKENHI Grant number: 16K10055 to H. T.).

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Authors and Affiliations

  1. Department of Pediatrics, Hirosaki University Hospital, Hirosaki, Japan

    Tomomi Aizawa, Koji Hirono, Shojiro Watanabe, Koji Tsugawa & Hiroshi Tanaka

  2. Department of Vascular Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Tadaatsu Imaizumi

  3. Department of School Health Science, Hirosaki University Faculty of Education, Hirosaki, 036-8560, Japan

    Hiroshi Tanaka

Authors
  1. Tomomi Aizawa
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  2. Tadaatsu Imaizumi
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  3. Koji Hirono
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  4. Shojiro Watanabe
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  5. Koji Tsugawa
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  6. Hiroshi Tanaka
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Corresponding author

Correspondence to Hiroshi Tanaka.

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The authors declare that there is no conflict of interest.

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This study was not involved human subjects which required ethical approval.

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Aizawa, T., Imaizumi, T., Hirono, K. et al. Chloroquine attenuates TLR3-mediated plasminogen activator inhibitor-1 expression in cultured human glomerular endothelial cells. Clin Exp Nephrol 23, 448–454 (2019). https://doi.org/10.1007/s10157-018-1659-y

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  • DOI: https://doi.org/10.1007/s10157-018-1659-y

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