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BMAL1 regulates tubular epithelial-derived exosomal miR-27a-3p to inhibits macrophage-myofibroblast transition thus alleviating ischemia/reperfusion induced renal fibrosis

ABSTRACT: Exosomal microRNAs are closely related to the progression of renal fibrosis. The circadian rhythm gene BMAL1 is thought to be involved in a variety of diseases. However, how BMAL1 regulates renal fibrosis induced by ischemia-reperfusion injury (IRI) has not been determined. We first examined BMAL1 expression, exosomal expression, the macrophage-to-myofibroblast transition (MMT) ratio, and renal fibrosis levels in mice with renal IRI. The results showed that renal IRI induced a decrease in BMAL1 expression, along with an increase in exosome secretion, MMT formation and renal fibrosis. Next, we overexpressed BMAL1 in mouse kidneys and found that BMAL1 inhibited IRI-induced MMT and fibrosis. We confirmed that exosome-mediated MMT directly aggravated renal fibrosis and that this process was directly regulated by BMAL1 through in vivo and in vitro exosome uptake experiments and Rab27a knockout mouse construction. High-throughput miRNA sequencing of exosomes derived from TCMK-1 cells and ChIP assays were used to confirm that exosomal miR-27a-3p was downregulated after hypoxia-reoxygenation (H/R) treatment and that BMAL1 directly promoted the transcription of miR-27a-3p. We identified TGFBR1 as the target gene of miR-27a-3p by transfecting cells with miR-27a-3p mimics and miR-27a-3p inhibitors and performing dual luciferase assays. Finally, we transfected cells with si-TGFBR1 and identified the TGFBR1/smad3 pathway as a key pathway for regulating MMT and renal fibrosis regulated by tubular epithelium-derived exosomal miR-27a-3p. Our findings indicated that BMAL1 was suppressed in renal IRI, which promoted MMT and renal fibrosis by upregulating the level of miR-27a-3p in tubular epithelial-derived exosomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE261069 | GEO | 2026/06/10

REPOSITORIES: GEO

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BMAL1 regulates tubular epithelial-derived exosomal miR-27a-3p to inhibits macrophage-myofibroblast transition thus alleviating ischemia/reperfusion induced renal fibrosis

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