Adipose-Derived Mesenchymal Stem Cells Extracellular Vesicles Attenuate AKI by TXNIP-IKKα/NFκB

Background: Extracellular vesicles produced by mesenchymal stem cells (MSC-EVs) have received widespread attention as a cell-free treatment option for acute kidney injury (AKI). The underlying processes and capabilities of MSC-EVs in mitigating kidney injury remain largely unclear. Methods: Establishment of AKI mouse models by cisplatin tail vein injection. AKI mice were further randomized to receive saline or adipose-derived mesenchymal stem cells-extracellular vesicles (AMSC-EVs) (50 μg) or AMSC-EVs (100 μg) into the tail vein. Ninety-six hours after injury, mice were sacrificed, and kidney tissue and blood samples were obtained for paraffin embedding and immunoblotting. To investigate the relationship between AMSC-EVs and kidney-resident macrophages, CX3CR1+ macrophage-specific conditional knockout mice (CX3CR1-Cre+/-; Rosa26-LSL-DTR+/-). In addition, a TXNIP (thioredoxin-interacting protein) overexpression assay was performed to analyze macrophage polarization and TXNIP-IKKα/NFκB signaling pathway expression. Results: In mice, AMSC-EVs reduce tubular injury and ameliorate cisplatin-induced AKI in a dose-dependent manner. However, in the CX3CR1+ macrophage ablation group, AKI mice exhibited more severe tubular lesions compared to littermates, suggesting that the therapeutic effect of AMSC-EVs was diminished after CX3CR1+ ablation. At the same time, AMSC-EVs promote the polarization of kidney-resident macrophages to repairing M2 macrophages, leading to increased production of anti-inflammatory factors and subsequently altering the inflammatory microenvironment in renal tubular cells, thereby promoting the self-healing process in AKI mice. Mechanistically, AMSC-EVs inhibit the protein expression of TXNIP-IKKα/NFκB in kidney-resident macrophages. Finally, overexpression of TXNIP can attenuate the protective effect of AMSC-EVs on kidney-resident macrophages. Conclusion: Our findings suggest that AMSC-EVs regulate the polarization of kidney-resident macrophages after cisplatin-induced AKI and promote renal self-recovery through the TXNIP-IKKα/NFκB signaling pathway. Funding: Clinical Revenue Support