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Comparison of miRNA between normal rat plasma exosomes and melatonin pretreated rat plasma exosomes

ABSTRACT: Stroke places a huge burden on society today, and great of studies were devoted for seeking safe and effective therapeutic strategy to improve the prognosis of stroke. Plasma exosome has exhibited its therapeutic potential against ischemia and reperfusion injury via ameliorating inflammation. To enhance therapeutic potential in patients with ischemic injury, we isolated exosomes from melatonin pretreated rat plasma and assessed the neurological protective effect in a rat model of focal cerebral ischemia. Treatment with melatonin enhanced plasma exosome therapeutic effect against ischemia induced inflammatory response and inflammasome mediated pyroptosis. In addition, we confirmed ischemic stroke induced pyroptotic cell death mainly occurred in microglia, while administration of melatonin treated exosome further effectively decreased infract volume and improved function recovery via regulation of TLR-4/NF-κB signaling pathway. Finally, the altered miRNAs profile in melatonin treated plasma exosomes demonstrated the regulatory mechanisms. This study suggests plasma exosome with melatonin pretreatment might be a more effective strategy for patients with ischemic brain injury. Further exploration of key molecules in plasma exosome may devote more therapeutic value for cerebral ischemic injury.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE147578 | GEO | 2020/03/27

REPOSITORIES: GEO

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Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.

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Comparison of miRNA between normal rat plasma exosomes and melatonin pretreated rat plasma exosomes

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