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CircACTR2 in macrophages promotes renal fibrosis by activating macrophage inflammation and epithelial–mesenchymal transition of renal tubular epithelial cells

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Abstract

The crosstalk between macrophages and tubular epithelial cells (TECs) actively regulates the progression of renal fibrosis. In the present study, we revealed the significance of circular RNA ACTR2 (circACTR2) in regulating macrophage inflammation, epithelial–mesenchymal transition (EMT) of TECs, and the development of renal fibrosis. Our results showed UUO-induced renal fibrosis was associated with increased inflammation and EMT, hypertrophy of contralateral kidney, up-regulations of circACTR2 and NLRP3, and the down-regulation of miR-561. CircACTR2 sufficiently and essentially promoted the activation of NLRP3 inflammasome, pyroptosis, and inflammation in macrophages, and through paracrine effect, stimulated EMT and fibrosis of TECs. Mechanistically, circACTR2 sponged miR-561 and up-regulated NLRP3 expression level to induce the secretion of IL-1β. In TECs, IL-1β induced renal fibrosis via up-regulating fascin-1. Knocking down circACTR2 or elevating miR-561 potently alleviated renal fibrosis in vivo. In summary, circACTR2, by sponging miR-561, activated NLRP3 inflammasome, promoted macrophage inflammation, and stimulated macrophage-induced EMT and fibrosis of TECs. Knocking down circACTR2 and overexpressing miR-561 may, thus, benefit the treatment of renal fibrosis.

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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by General Project of Health Committee of Hunan Province (202103050649) and Natural Science Funds for Youth Fund of Hunan Province (2018JJ3781).

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Authors and Affiliations

  1. Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People’s Republic of China

    Hua Fu, Yong-Hong Gu, Juan Tan & Ye-Ning Yang

  2. Department of Gastrointestinal Surgery, Third Xiangya Hospital, Central South University, No 138, Tongzipo Road, Yuelu, Changsha, 410013, Hunan, People’s Republic of China

    Guo-Hui Wang

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  1. Hua Fu
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Correspondence to Guo-Hui Wang.

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All animal procedures received approval from the Animal Care and Use Committee of the third Xiangya Hospital, Central South University (Changsha, China).

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Fu, H., Gu, YH., Tan, J. et al. CircACTR2 in macrophages promotes renal fibrosis by activating macrophage inflammation and epithelial–mesenchymal transition of renal tubular epithelial cells. Cell. Mol. Life Sci. 79, 253 (2022). https://doi.org/10.1007/s00018-022-04247-9

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  • DOI: https://doi.org/10.1007/s00018-022-04247-9

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