Curcumin‐induced exosomal FTO from bone marrow stem cells alleviates sepsis‐associated acute kidney injury by modulating the m6A methylation of OXSR1

Abstract

Curcumin and bone marrow stem cells (BMSCs)‐derived exosomes are considered to be useful for the treatment of many human diseases, including sepsis‐associated acute kidney injury (SA‐AKI). However, the role and underlying molecular mechanism of curcumin‐loaded BMSCs‐derived exosomes in the progression of SA‐AKI remain unclear. Exosomes (BMSCs‐EXOCurcumin or BMSCs‐EXOControl) were isolated from curcumin or DMSO‐treated BMSCs, and then co‐cultured with LPS‐induced HK2 cells. Cell proliferation and apoptosis were determined by cell counting kit 8 (CCK8) assay, 5‐ethynyl‐2‐deoxyuridine (EdU) assay, and flow cytometry. Enzyme‐linked immunosorbent assay (ELISA) was used for examining inflammatory factors. The levels of SOD, MDA, and ROS were tested to assess oxidative stress. The levels of fat mass and obesity‐associated protein (FTO) and oxidative stress responsive 1 (OXSR1) were detected by quantitative real‐time PCR and western blot. Methylated RNA immunoprecipitation (MeRIP) assay and RNA immunoprecipitation (RIP) assay were used for measuring the interaction between FTO and OXSR1. BMSCs‐EXOCurcumin treatment could inhibit LPS‐induced HK2 cell apoptosis, inflammation, and oxidative stress. FTO was downregulated in SA‐AKI patients and LPS‐induced HK2 cells, while was upregulated in BMSCs‐EXOCurcumin. Exosomal FTO from curcumin‐induced BMSCs suppressed apoptosis, inflammation, and oxidative stress in LPS‐induced HK2 cells. FTO decreased OXSR1 expression through m6A modification, and the inhibitory effect of FTO on LPS‐induced HK2 cell injury could be eliminated by OXSR1 overexpression. In animal experiments, BMSCs‐EXOCurcumin alleviated kidney injury in SA‐AKI mice models by regulating FTO/OXSR1 axis. In conclusion, exosomal FTO from curcumin‐induced BMSCs reduced OXSR1 expression to alleviate LPS‐induced HK2 cell injury and improve kidney function in CLP‐induced mice models, providing a new target for SA‐AKI.