BMAL1 regulates tubular epithelial-derived exosomal miR-27a-3p to inhibit macrophage–myofibroblast transition and alleviate ischemia/reperfusion-induced renal fibrosis

Jun 5, 2026Theranostics

BMAL1 controls kidney cell signals that reduce scar-forming cell changes and ease kidney scarring after blood flow injury

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Abstract

Renal ischemia‒reperfusion injury increased exosome secretion, which is associated with enhanced macrophage-to-myofibroblast transition and renal fibrosis.

Overexpression or knockout of BMAL1 significantly reduced IRI-induced macrophage-to-myofibroblast transition and fibrotic progression.
Exosomes from hypoxia-reoxygenation-treated tubular epithelial cells exacerbated macrophage-to-myofibroblast transition and renal fibrosis in an IRI model.
Tubular-specific overexpression of BMAL1 or inhibition of exosome secretion markedly attenuated both macrophage-to-myofibroblast transition and fibrosis progression.
BMAL1 enhances transcription by binding directly to the promoter region, impacting exosomal levels and their effects on macrophages.
Exosomal miR-27a-3p targets TGFBR1 mRNA in macrophages, potentially suppressing the signaling pathway involved in macrophage-to-myofibroblast transition and renal fibrosis.

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RATIONALE: During ischemia‒reperfusion injury (IRI),has been shown to alleviate inflammation and kidney damage. However, the function of the tubular epithelium-macrophage interaction mediated byin IRI-induced renal fibrosis is still unclear. BMAL1BMAL1

METHODS: A mouse model of kidney-specificoverexpression was developed to study howaffects renal fibrosis, exosome production, and the macrophage-to-myofibroblast transition (MMT). The role of exosomes in the MMT and renal fibrosis was examined in bothandstudies using exosomes extracted from TCMK-1 cells. Exosomes from-overexpressing TCMK-1 cells subjected to hypoxia-reoxygenation (H/R) were isolated and subjected to miRNA sequencing to identify key exosomal components. Exosomalregulation byand its downstream effects onin macrophages were investigated using a variety of experimental methods. To assess the effect of exosomalon MMT and renal fibrosis, additionalandinvestigations were conducted. BMAL1BMAL1in vitro in vivo BMAL1miR-27a-3p BMAL1TGFBR1/smad3miR-27a-3p in vitro in vivo

RESULTS: Renal IRI increased exosome secretion, promoted MMT, and exacerbated renal fibrosis, whereasoverexpression orknockout 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, elevation of exosomallevels, or inhibition of exosome secretion significantly attenuated the progression of both MMT and fibrosis. Mechanistic studies demonstrated thatbinds directly to thepromoter region, enhancing transcription. Exosomalsubsequently targetsmRNA in macrophages, thereby suppressing thesignaling pathway and ultimately attenuating MMT and renal fibrosis. BMAL1Rab27a BMAL1miR-27a-3p BMAL1miR-27a-3p miR-27a-3p TGFBR1TGFBR1/smad3

CONCLUSIONS: expression was suppressed in IRI, which promoted MMT and renal fibrosis via the exosomal-pathway. Targeting this signaling pathway may offer a potential therapeutic strategy for alleviating IRI-induced renal fibrosis. BMAL1miR-27a-3p TGFBR1/smad3

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BMAL1 regulates tubular epithelial-derived exosomal miR-27a-3p to inhibit macrophage–myofibroblast transition and alleviate ischemia/reperfusion-induced renal fibrosis

Abstract

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