Open Access

Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation

  • Authors:
    • Linfeng Zheng
    • Wenjuan Mei
    • Jing Zhou
    • Xin Wei
    • Zhijuan Huang
    • Xiaozhen Lin
    • Li Zhang
    • Wei Liu
    • Qian Wu
    • Jinhong Li
    • Yan Yan
  • View Affiliations

  • Published online on: February 15, 2024     https://doi.org/10.3892/etm.2024.12430
  • Article Number: 142
  • Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)‑treated HK‑2 cells and murine peritoneal‑derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase‑1 and maturation of IL‑1β by suppressing NLRP3 inflammasome activation in H/R‑treated HK‑2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated activation of the NLRP3 inflammasome.
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April-2024
Volume 27 Issue 4

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Spandidos Publications style
Zheng L, Mei W, Zhou J, Wei X, Huang Z, Lin X, Zhang L, Liu W, Wu Q, Li J, Li J, et al: Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation. Exp Ther Med 27: 142, 2024
APA
Zheng, L., Mei, W., Zhou, J., Wei, X., Huang, Z., Lin, X. ... Yan, Y. (2024). Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation. Experimental and Therapeutic Medicine, 27, 142. https://doi.org/10.3892/etm.2024.12430
MLA
Zheng, L., Mei, W., Zhou, J., Wei, X., Huang, Z., Lin, X., Zhang, L., Liu, W., Wu, Q., Li, J., Yan, Y."Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation". Experimental and Therapeutic Medicine 27.4 (2024): 142.
Chicago
Zheng, L., Mei, W., Zhou, J., Wei, X., Huang, Z., Lin, X., Zhang, L., Liu, W., Wu, Q., Li, J., Yan, Y."Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated NLRP3 inflammasome activation". Experimental and Therapeutic Medicine 27, no. 4 (2024): 142. https://doi.org/10.3892/etm.2024.12430