Exosomal miR-145-5p from BMSCs alleviates AKI-induced renal fibrosis via KLHL12/KHSRP-mediated m6A-dependent repression of FLI-1

Pericyte to myofibroblast transformation is a key driver of renal fibrosis following acute kidney injury (AKI). Exosomes, miRNAs, and bone mesenchymal stem cells (BMSCs) are important in alleviating AKI renal fibrosis. We proposed to explore the role of engineering exosomes rich in miR-145-5p and correlated with KLHL12/KHSRP in AKI-induced pericytes-mediated fibrosis in the present study. Rat perirenal cells were isolated and cultured. Engineering exosomes rich in miR-145-5p derived from BMSCs were obtained through cell transfection technology. AKI rat model and Hypoxia/Reoxygenation (HR) induced perirenal cells injury model were established. Dual luciferase reporter gene, MeRIP, and Co-immunoprecipitation were performed to validate miR-145-5p targeting KLHL12 and its downstream molecules including KHSRP and FLI-1. Renal function, apoptosis and pyroptosis, fibrosis-related proteins were detected through biochemistry, immunohistochemistry, immunofluorescence, and transmission electron microscopy to explore the functional role of the miR-145-5p/ KLHL12/KHSRP/FLI-1 axis in cellular and animal models. According to our findings, pericyte-myoblast transformation contributed to AKI-induced fibrosis in vivo and HR-induced fibrosis along with apoptosis and pyroptosis in vitro. MiR-145-5p down-regulated KLHL12 expression by targeting its 3’UTR to improve perirenal cells-mediated fibrosis. KLHL12 might downregulate KHSRP to increase FLI-1 expression by promoting FLI-1 mRNA stability in AKI-induced fibrosis mediated by perirenal cells. These findings indicate that miR-145-5p enriched in BMSC derived engineered exosomes may suppress KLHL12 expression to up-regulate KHSRP and then down-regulate FLI-1 by m6A to attenuate perirenal cells-mediated fibrosis. 1. BMSC-derived exosomal miR-145-5p targets KLHL12 in renal pericytes to alleviate AKI-induced fibrosis. 2. miR-145-5p downregulates KLHL12, enhancing KHSRP to promote FLI-1 mRNA decay via m6A modification. 3. This axis inhibits pericyte-to-myofibroblast transition, apoptosis, and pyroptosis, restoring renal function. 4. Engineered miR-145-5p-enriched exosomes offer a promising cell-free therapy for AKI-to-CKD progression.