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Novel role of miR-18a-5p and Galanin in rat lung ischemia-reperfusion mediated response

ABSTRACT: Lung ischemia-reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage, is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNA) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high throughput approach and evaluated distinct set of miRNAs that may play a role in response to IR in rat lung tissue. Top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an in vitro model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. MiR-18a-5p plays a role in IR mediated apoptosis, ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: Nuclear factor-erythroid 2 related factor (Nrf2) which in turn may regulate the expression of miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerate the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p in the same. This study will have important clinical and therapeutic implications for and during transplantation procedures.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE161520 | GEO | 2020/11/19

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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Novel role of miR-18a-5p and Galanin in rat lung ischemia-reperfusion mediated response

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