micro-RNA-486-5p protects against kidney ischemic injury and modifies the apoptotic transcriptome in proximal tubules
Jose L Viñas1, Matthew Spence1, Christopher J Porter2
1Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Abstract:
Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI.
Insights
MicroRNA-486-5p shows therapeutic potential for acute kidney injury (AKI). This study demonstrates that miR-486-5p improves kidney function and reduces injury markers in preclinical models of AKI.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Acute kidney injury (AKI) is a significant clinical challenge with limited effective treatments.
- MicroRNAs (miRs) are implicated in AKI pathogenesis, but their specific roles and transcriptomic effects remain incompletely understood.
- Previous work indicated that exosomes enriched with miR-486-5p protected against ischemic AKI in mice.
Purpose of the Study:
- To investigate the direct therapeutic effects of miR-486-5p in a mouse model of kidney ischemia-reperfusion injury (IRI).
- To elucidate the impact of miR-486-5p and exosomes on the kidney transcriptome in proximal tubules and endothelial cells following IRI.
- To determine the molecular mechanisms underlying miR-486-5p's protective effects in AKI.
Main Methods:
- Utilized a mouse model of kidney ischemia-reperfusion injury (IRI).
- Administered miR-486-5p mimic to AKI mice and assessed kidney function and histology.
- Employed RNA-sequencing (RNA-Seq) to compare the transcriptomic changes induced by miR-486-5p and exosomes in isolated proximal tubules and kidney endothelial cells 24 hours post-IRI.
- Quantified miR-486-5p levels and analyzed downstream signaling pathways, including PTEN/Akt.
Main Results:
- Injection of miR-486-5p mimic improved plasma creatinine, reduced histological injury, neutrophil infiltration, and apoptosis in AKI mice.
- miR-486-5p successfully increased its levels in proximal tubules and endothelial cells.
- miR-486-5p targeted and inhibited phosphatase and tensin homolog (PTEN), leading to activation of protein kinase B (Akt).
- In proximal tubules, both miR-486-5p and exosomes downregulated genes in the tumor necrosis factor (TNF) pathway and altered apoptotic gene expression.
- In endothelial cells, miR-486-5p and exosomes modulated genes involved in metabolic processes, but not the TNF pathway.
Conclusions:
- miR-486-5p demonstrates significant therapeutic potential for mitigating kidney damage in acute kidney injury.
- The protective effects of miR-486-5p involve the inhibition of PTEN and activation of the Akt pathway.
- miR-486-5p and exosomes exert distinct transcriptomic effects on kidney proximal tubules and endothelial cells during AKI recovery.
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