Leocarpinolide B通过巨噬细胞外泌体miR-204-5p/TFAM轴减轻AKI-CKD转化中的肾小管上皮线粒体功能障碍

Abstract

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a distinct clinical syndrome critically driven by mitochondrial dysfunction. Emerging evidence suggests that exosome-dependent crosstalk between macrophages and renal tubular epithelial cells (RTECs) facilitates AKI-CKD transition. Leocarpinolide B (LB), a bioactive compound derived from the traditional Chinese medicine Siegesbeckiae Herba , exhibits potent anti-inflammatory activity in macrophages. However, the renoprotective role of LB against macrophage-mediated AKI-CKD transition and the underlying mechanisms involved remain unclear. In this study, we demonstrated that lipopolysaccharide (LPS)-stimulated macrophages exacerbated mitochondrial dysfunction and inflammation in RTECs, whereas LB suppressed inflammatory crosstalk between macrophages and RTECs. Strikingly, comparable attenuation of RTECs injury was observed using isolated exosomal fractions. Furthermore, inhibition of exosome secretion alleviated mitochondrial impairment and suppressed inflammation-fibrosis progression in RTECs. miRNA sequencing revealed a significantly elevation of miR-204-5p in serum exosomes from AKI patients. Notably, LB treatment counteracted this pathogenic miRNA upregulation in injured RTECs via an exosome-mediated pathway, thereby directly linking its reno-protective function to the exosomal miR-204-5p modulation. Subsequent bioinformatics analysis and luciferase reporter assays identified mitochondrial transcription factor A (TFAM) as a direct target of miR-204-5p. Functionally, overexpression of miR-204-5p in RTECs abrogated the protective effects of LB against mitochondrial dysfunction and cellular injury, whereas miR-204-5p knockdown synergistically enhanced LB-mediated renoprotection. In a murine folic acid (FA)-induced AKI-CKD model, the therapeutic efficacy of LB was substantially enhanced by a hyaluronic acid (HA)-functionalized liposomal nanoplatform, which facilitated targeted