Human bone marrow mesenchymal stem cell-derived extracellular vesicles reduce inflammation and pyroptosis in acute kidney injury via miR-223-3p/HDAC2/SNRK
- Inflamm Res. 2023 Jan 14;1-24. doi: 10.1007/s00011-022-01653-4.
- 1. Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China.
- 2. Department of Emergency, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
- 3. Department of Nuclear Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
- 4. Health Management Center, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
- 5. Department of Rheumatology and Immunology, Hunan Province Mawangdui Hospital, Changsha, 410016, Hunan, People's Republic of China.
- 6. Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China. [email protected].
Objective: Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) have been demonstrated as a potential therapeutic agent in acute kidney injury (AKI). However, little is known about the mechanisms of action of BMSC-derived EVs in AKI. Based on this, our research was designed to investigate the mechanism behind BMSC-derived EVs controlling inflammation and Pyroptosis during AKI.
Methods: Peripheral blood from AKI patients was used for detection of MicroRNA (miR)-223-3p, HDAC2, and SNRK expression. An AKI rat model was established, and HK-2 cell injury was induced by lipopolysaccharide (LPS) to establish a cellular model. Co-culture with BMSC-derived EVs and/or gain- and loss-of-function assays were conducted in LPS-treated HK-2 to evaluate the functions of BMSCs-EVs, miR-223-3p, HDAC2, and SNRK. AKI rats were simultaneously injected with EVs and short hairpin RNAs targeting SNRK. The interactions among miR-223-3p, HDAC2, and SNRK were evaluated by RIP, ChIP, and dual-luciferase gene reporter assays.
Results: Patients with AKI had low miR-223-3p and SNRK expression and high HDAC2 expression in peripheral blood. Mechanistically, miR-223-3p targeted HDAC2 to accelerate SNRK transcription. In LPS-treated HK-2 cells, BMSCs-EVs overexpressing miR-223-3p increased cell viability and diminished cell Apoptosis, KIM-1, LDH, IL-1β, IL-6, TNF-α, NLRP3, ASC, cleaved Caspase-1, and IL-18 expression, and GSDMD cleavage, which was nullified by HDAC2 overexpression or SNRK silencing. In AKI rats, BMSCs-EV-shuttled miR-223-3p reduced CRE and BUN levels, Apoptosis, inflammation, and Pyroptosis, which was abrogated by SNRK silencing.
Conclusion: Conclusively, BMSC-derived EV-encapsulated miR-223-3p mitigated AKI-induced inflammation and Pyroptosis by targeting HDAC2 and promoting SNRK transcription.