Abstract: SA-PO109
Endothelial-Derived miR-17~92 Protects Against Renal Ischemia-Reperfusion Injury
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
- Chiba, Takuto, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Bodnar, Andrew J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Hemker, Shelby L., University of Pittsburgh - Rangos Research Center, Pittsburgh, Pennsylvania, United States
- Mukherjee, Elina, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Phua, Yu Leng, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Shaikh, Kai J., University of California, Berkeley, California, United States
- Sanders, Brandon T., Claflin University , Orangeburg, South Carolina, United States
- Ho, Jacqueline, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Sims-Lucas, Sunder, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Acute kidney injury (AKI), resulting from renal ischemia reperfusion injury (IRI) among others, is an independent predictor of morbidity and mortality, and is identified in as many as 50% of ICU patients. Damage to the renal microvasculature is a hallmark of renal IRI. miR-17~92 encodes 6 polycistronic microRNAs that show potent pro-angiogenic capacity by targeting anti-angiogenic factors. The function of miR-17~92 in renal microvasculature after renal IRI remains unknown. We hypothesized that endothelial-specific miR-17~92 mediates endothelial repair and kidney recovery after renal IRI.
Methods
Endothelial-specific miR-17~92 knockout (miR-17~92endo-/-) transgenic mice were generated and a renal IRI model was performed. Mice were monitored for the development of AKI using serum chemistries, histology, and markers of renal tubular injury. The renal vasculature and infiltrating macrophages post-injury were evaluated using multiple markers.
Results
We demonstrate that miR-17, miR-18a, miR-19b and miR-20a in the miR-17~92 cluster are up-regulated in CD31+ renal endothelial cells following renal IRI. Loss of miR-17~92 in endothelial cells does not affect renal vascular development and renal function in adult mice. Following renal IRI, miR-17~92endo-/- mice had worse renal dysfunction and epithelial damage, and exhibited up-regulation of the injury marker NGAL in proximal tubules compared to the controls. miR-17~92endo-/- kidneys had decreased Endomucin-positive renal microvasculature post renal IRI. miR-17~92endo-/- kidneys upregulated the potent anti-angiogenic factor Thrombospondin-1 (TSP1) in a subset of Endomucin-positive renal microvasculature. miR-17~92endo-/- kidneys also had increased F4/80-positive infiltrating macrophages post renal IRI along with up-regulation of multiple macrophage markers in its kidneys.
Conclusion
These data suggest that miR-17~92 in renal endothelial cells confers protection from damage in the renal microvasculature during renal IR mediated AKI by targeting an anti-angiogenic factor TSP1. This, in turn, mitigates hypoxic damage in tubular epithelial cells and down-regulates inflammatory activation following injury.
Funding
- NIDDK Support