Abstract: SA-PO106
Administration of miR-486-5p Protects Against Kidney Ischemic Injury and Alters the Transcriptome in Male and Female Mice
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Vinas, Jose L., Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Spence, Matthew, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Zimpelmann, Joe A., Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Douvris, Adrianna, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Gutsol, Alex, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Campbell, Pearl Ann, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Porter, Christopher J., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Burns, Kevin D., Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
Background
Ischemia-reperfusion is a common cause of acute kidney injury (AKI), and no treatments exist to restore function. We showed that cord blood endothelial colony forming cells (ECFCs) release exosomes (enriched in miR-486-5p) that are protective against ischemic AKI in male mice. This response involves inhibition of phosphatase and tensin homolog (PTEN, a target of miR-486-5p) and Akt activation. Here, we studied effects of direct administration of miR-486-5p to mice with AKI, and defined sex differences.
Methods
Kidney injury was induced in mice by 30-minute bilateral renal vascular clamping followed by reperfusion and sacrifice at 24 or 48 hrs. ECFC exosomes, miR-486-5p mimic (in cationic lipid), or scrambled miR were injected i.v. at the start of reperfusion. Kidney endothelial cells and proximal tubules were isolated for transcriptomic analyses.
Results
Male and female mice treated with miR-486-5p mimic at the time of reperfusion had increased miR-486-5p levels in kidney endothelial cells and proximal tubules, liver and spleen (P<0.01, n=8), but not in lung, heart or brain. In male or female mice with kidney ischemia-reperfusion, miR-486-5p mimic or exosomes significantly decreased serum Cr and urea, histologic injury, apoptosis, and neutrophil infiltration (n=8). Delivery of miR-486-5p reduced kidney PTEN protein expression, and increased Akt phosphorylation (P<0.05, n=6). Female mice were resistant to kidney injury compared to males, by all parameters (P<0.05 vs male), showed fewer differentially expressed genes compared to males, and had less gene variation with treatments. Kidney ischemia induced higher numbers of differentially expressed genes in tubules compared to endothelial cells. In male mice treated with miR-486-5p mimic, the expression of most tubular genes that were significantly changed with ischemia-reperfusion alone returned to levels close to sham.
Conclusion
Systemic delivery of miR-486-5p to male and female mice with AKI increases miR-486-5p levels in kidney endothelial cells and proximal tubules, and prevents ischemic injury. Female mice are resistant to AKI compared to males, and exhibit fewer differentially expressed genes. Changes in the kidney transcriptome with miR-486-5p may define pathways relevant to prevention of AKI in humans.
Funding
- Private Foundation Support