HUMSC-Derived Extracellular Vesicles Loaded with MicroRNA-183-5p Attenuate Sepsis-Induced Acute Kidney Injury by Downregulating THBS1 and Suppressing the TGF-β Pathway

<b>Objective</b>: This work aimed to elucidate the molecular mechanisms by which human umbilical cord mesenchymal stem cell (HUMSC)-derived extracellular vesicles (EVs) loaded with microRNA-183-5p (miR-183-5p) mitigate sepsis-induced acute kidney injury (AKI), focusing on the downregulation of thrombospondin-1 (THBS1) and suppression of the TGF-β pathway. <b>Methods:</b> A cecal ligation and puncture (CLP) model was established to induce sepsis-induced AKI in mice, and an in vitro injury model was generated by exposing human renal tubular epithelial cells (HK-2 cells) to lipopolysaccharide (LPS). miR-183-5p expression levels in injured tissues and cells were assessed using RT-qPCR. EVs were isolated from HUMSCs via ultracentrifugation, and miR-183-5p-loaded EVs were prepared using electroporation. These loaded EVs were then administered to mice to assess their impacts on renal function, histopathological alterations, and apoptosis. Bioinformatic prediction identified THBS1 as miR-183-5p's potential target, which was verified through miRNA mimic transfection, dual-luciferase reporter assays, and THBS1 overexpression rescue experiments. <b>Results:</b> miR-183-5p expression was reduced in both the sepsis-induced AKI mouse model and LPS-treated HK-2 cells. Administration of miR-183-5p-loaded EVs effectively reduced serum inflammatory cytokine levels, improved renal function, and reduced apoptosis, thereby alleviating sepsis-induced AKI in mice. miR-183-5p directly targeted and inhibited THBS1 expression, thereby reducing LPS-induced apoptosis in HK-2 cells. Further experiments revealed that THBS1 promoted inflammation and apoptosis through the activation of the TGF-β pathway. <b>Conclusion:</b> HUMSC-derived EVs loaded with miR-183-5p effectively mitigate sepsis-induced AKI by targeting THBS1 and inhibiting the TGF-β pathway, thereby reducing inflammation and apoptosis.