Theranostics · 2026
BMAL1 regulates tubular epithelial-derived exosomal miR-27a-3p to inhibit macrophage-myofibroblast transition and alleviate ischemia/reperfusion-induced renal fibrosis.
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Chen Wu, Zhao Sheng, Yang Songyuan, Yu Weimin, Rao Ting, Zhou Xiangjun, Ruan Yuan, Zou Fan, Cheng Fan, Li Wei
Аннотация
RATIONALE: During ischemia‒reperfusion injury (IRI), BMAL1 has been shown to alleviate inflammation and kidney damage. However, the function of the tubular epithelium-macrophage interaction mediated by BMAL1 in IRI-induced renal fibrosis is still unclear.
METHODS: A mouse model of kidney-specific BMAL1 overexpression was developed to study how BMAL1 affects renal fibrosis, exosome production, and the macrophage-to-myofibroblast transition (MMT). The role of exosomes in the MMT and renal fibrosis was examined in both in vitro and in vivo studies using exosomes extracted from TCMK-1 cells. Exosomes from BMAL1-overexpressing TCMK-1 cells subjected to hypoxia-reoxygenation (H/R) were isolated and subjected to miRNA sequencing to identify key exosomal components. Exosomal miR-27a-3p regulation by BMAL1 and its downstream effects on TGFBR1/smad3 in macrophages were investigated using a variety of experimental methods. To assess the effect of exosomal miR-27a-3p on MMT and renal fibrosis, additional in vitro and in vivo investigations were conducted.
RESULTS: Renal IRI increased exosome secretion, promoted MMT, and exacerbated renal fibrosis, whereas BMAL1 overexpression or Rab27a knockout significantly attenuated IRI-induced MMT and fibrotic progression. Exosomes derived from H/R-treated tubular epithelial cells further exacerbated MMT and renal fibrosis in an IRI model. Notably, tubular-specific overexpression of BMAL1, elevation of exosomal miR-27a-3p levels, or inhibition of exosome secretion significantly attenuated the progression of both MMT and fibrosis. Mechanistic studies demonstrated that BMAL1 binds directly to the miR-27a-3p promoter region, enhancing transcription. Exosomal miR-27a-3p subsequently targets TGFBR1 mRNA in macrophages, thereby suppressing the TGFBR1/smad3 signaling pathway and ultimately attenuating MMT and renal fibrosis.
CONCLUSIONS: BMAL1 expression was suppressed in IRI, which promoted MMT and renal fibrosis via the exosomal miR-27a-3p-TGFBR1/smad3 pathway. Targeting this signaling pathway may offer a potential therapeutic strategy for alleviating IRI-induced renal fibrosis.
METHODS: A mouse model of kidney-specific BMAL1 overexpression was developed to study how BMAL1 affects renal fibrosis, exosome production, and the macrophage-to-myofibroblast transition (MMT). The role of exosomes in the MMT and renal fibrosis was examined in both in vitro and in vivo studies using exosomes extracted from TCMK-1 cells. Exosomes from BMAL1-overexpressing TCMK-1 cells subjected to hypoxia-reoxygenation (H/R) were isolated and subjected to miRNA sequencing to identify key exosomal components. Exosomal miR-27a-3p regulation by BMAL1 and its downstream effects on TGFBR1/smad3 in macrophages were investigated using a variety of experimental methods. To assess the effect of exosomal miR-27a-3p on MMT and renal fibrosis, additional in vitro and in vivo investigations were conducted.
RESULTS: Renal IRI increased exosome secretion, promoted MMT, and exacerbated renal fibrosis, whereas BMAL1 overexpression or Rab27a knockout significantly attenuated IRI-induced MMT and fibrotic progression. Exosomes derived from H/R-treated tubular epithelial cells further exacerbated MMT and renal fibrosis in an IRI model. Notably, tubular-specific overexpression of BMAL1, elevation of exosomal miR-27a-3p levels, or inhibition of exosome secretion significantly attenuated the progression of both MMT and fibrosis. Mechanistic studies demonstrated that BMAL1 binds directly to the miR-27a-3p promoter region, enhancing transcription. Exosomal miR-27a-3p subsequently targets TGFBR1 mRNA in macrophages, thereby suppressing the TGFBR1/smad3 signaling pathway and ultimately attenuating MMT and renal fibrosis.
CONCLUSIONS: BMAL1 expression was suppressed in IRI, which promoted MMT and renal fibrosis via the exosomal miR-27a-3p-TGFBR1/smad3 pathway. Targeting this signaling pathway may offer a potential therapeutic strategy for alleviating IRI-induced renal fibrosis.