Abstract: SA-PO082
miR-486-5p Protects Against Ischemic AKI in Rat but Inhibits eNOS and Angiogenesis
Session Information
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
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., University of Ottawa, Ottawa, Ontario, Canada
- Gutsol, Alex, University of Ottawa, Ottawa, Ontario, Canada
- Burger, Dylan, University of Ottawa, Ottawa, Ontario, Canada
- Burns, Kevin D., University of Ottawa, Ottawa, Ontario, Canada
Background
Acute kidney injury (AKI) is a common complication of hospitalization for which no effective treatments exist. Patients with recovered AKI are at increased risk of progressive chronic kidney disease (CKD). In ischemia-reperfusion (IR) AKI, endothelial injury contributes to capillary rarefaction and development of tubulointerstitial fibrosis. We previously showed that microRNA (miR)-486-5p protects against IR AKI in mice associated with targeting of phosphatase and tensin homolog (PTEN), activation of Akt, and downregulation of genes involved in apoptosis and tumor necrosis factor signaling in proximal tubular cells. However, the effects of miR-486-5p in rat IR AKI and on endothelial cell injury are unknown.
Methods
Kidney ischemic injury was induced in male rats by 45-min bilateral renal artery clamping followed by reperfusion, with outcomes after 24hr, 48hr, and 4 weeks. Lipid-encapsulated miR-486-5p (0.5mg/kg) was administered via tail vein injection at the start of reperfusion. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-486-5p (1nM), and angiogenesis was evaluated with matrigel-based tube formation assay.
Results
Administration of miR-486-5p to rats with IR injury significantly protected against AKI with normalization of plasma Cr and BUN (p<0.05, n=3), and reduced KIM-1 levels (p<0.01, n=3) at 24 and 48hr. In rats with AKI, miR-486-5p did not affect plasma Cr after 4 weeks, compared to sham rats or rats with AKI alone. However, in rats with AKI, miR-486-5p protected against the development of interstitial fibrosis and tubular atrophy at 4 weeks. In HUVECs, miR-486-5p decreased the expression of PTEN (p<0.05, N=4), and endothelial nitric oxide synthase (eNOS) (p<0.001, N=4). Matrigel-based network formation assay showed that miR-486-5p reduced the angiogenic activity of normoxic HUVECs compared to untreated cells or cells treated with scramble miRNA (p<0.05, N=4).
Conclusion
These data suggest that miR-486-5p prevents ischemic AKI in rats, and protects against the development of CKD after AKI. However, miR-486-5p may affect endothelial function with reduced angiogenic activity, possibly related to decreased eNOS expression. Although miR-486-5p shows promise as a therapeutic tool in AKI, long-term effects on kidney microvascular structure and function in vivo require further study.
Funding
- Government Support – Non-U.S.