Abstract: FR-PO188
miR-486-5p Protects Against Ischemic AKI and Prevents Transition to CKD
Session Information
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Douvris, Adrianna, University of Ottawa, Ottawa, Ontario, Canada
- Vinas, Jose L., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Zimpelmann, Joe A., University of Ottawa, Ottawa, Ontario, Canada
- Gutsol, Alex, University of Ottawa, Ottawa, Ontario, Canada
- Burger, Dylan, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Burns, Kevin D., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Background
Recovery from acute kidney injury (AKI) is associated with increased risk for progressive chronic kidney disease (CKD). We previously showed that microRNA (miR)-486-5p protects against kidney ischemia-reperfusion (IR) injury in mice, with targeting of phosphatase and tensin homolog (PTEN) and downregulation of proximal tubular genes involved in apoptosis and tumor necrosis factor signaling. In cultured human endothelial cells however, miR-486-5p inhibits endothelial nitric oxide synthase (eNOS) expression. Here, we studied the effects of miR-486-5p on IR AKI and CKD development in rats with a focus on vasculature.
Methods
Kidney IR injury was induced in male rats by bilateral renal pedicle clamping followed by reperfusion. Lipid-encapsulated miR-486-5p (0.5mg/kg) was injected i.v. at the start of reperfusion. Outcomes were assessed after 24hr and 10 weeks. Kidney blood flow was measured by laser doppler flowmetry. Endothelium-dependent mesenteric artery reactivity was evaluated by myography.
Results
In rats with IR AKI, miR-486-5p preserved regional kidney blood flow at 24hr (p<0.01,n=7) and prevented increases in plasma Cr (p<0.001,n=10), neutrophil and macrophage infiltration, and apoptosis. miR-486-5p had no effect on kidney PTEN expression, but inhibited IR-induced expression of eNOS and intercellular adhesion molecule (ICAM)-1. At 10 weeks, while rats with IR alone had normal plasma Cr, kidneys displayed decreased peritubular capillary density with increased interstitial collagen, α-smooth muscle actin+ myofibroblasts, and F4/80+ macrophages. These changes were inhibited by miR-486-5p (CD31,collagen p<0.0001,n=6-8). Although blood pressure was similar across rat groups, IR inhibited endothelium-dependent vasorelaxation in mesenteric arteries at 10 weeks, which was prevented by miR-486-5p. Delayed administration of 2 doses of miR-486-5p (96hr, 3 weeks after IR) had no effect on capillary density, kidney fibrosis, blood pressure, or endothelial function.
Conclusion
In rats, early administration of miR-486-5p prevents kidney IR injury and preserves regional blood flow despite reduction in eNOS expression. miR-486-5p also protects against CKD development and associated endothelial dysfunction. The results suggest that miR-486-5p is a promising therapy for the prevention of ischemic AKI and its complications.
Funding
- Private Foundation Support