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

Ting Yang; Hui Yu; Zheng Xie

doi:10.1002/kjm2.12923

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

Kaohsiung J Med Sci. 2024 Dec 30:e12923. doi: 10.1002/kjm2.12923. Online ahead of print.

Authors

Ting Yang¹, Hui Yu¹, Zheng Xie¹

Affiliation

¹ Department of Emergency Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China.

PMID: 39739936
DOI: 10.1002/kjm2.12923

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-EXO^Curcumin or BMSCs-EXO^Control) 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-EXO^Curcumin 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-EXO^Curcumin. 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-EXO^Curcumin 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.

Keywords: FTO; OXSR1; bone marrow stem cells; exosomes; sepsis‐associated AKI.