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Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury

Takuto Chiba, Débora M. Cerqueira, Yao Li, Andrew J. Bodnar, Elina Mukherjee, Katherine Pfister, Yu Leng Phua, Kai Shaikh, Brandon T. Sanders, Shelby L. Hemker, Patrick J. Pagano, Yijen L. Wu, Jacqueline Ho and Sunder Sims-Lucas
JASN March 2021, 32 (3) 553-562; DOI: https://doi.org/10.1681/ASN.2020050717
Takuto Chiba
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Débora M. Cerqueira
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Yao Li
2Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Andrew J. Bodnar
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Elina Mukherjee
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Katherine Pfister
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Yu Leng Phua
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Kai Shaikh
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Brandon T. Sanders
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Shelby L. Hemker
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Patrick J. Pagano
2Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Yijen L. Wu
3Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Jacqueline Ho
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Sunder Sims-Lucas
1Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
2Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Significance Statement

Regulation of endothelial cells is important in many biologic processes, including development, organ function, and disease. The kidney vasculature is highly sensitive to hypoxic injury and has a limited capacity for repair. AKI as a result of decreased blood flow is common, and there are no current therapies. MicroRNAs are small noncoding RNAs that inhibit expression of target genes. Endothelial-derived miR-17∼92 is a cluster of microRNAs critical for endothelial function and repair during AKI in mice. Furthermore, pharmacologic treatment with mimics of the cluster mitigates AKI, promoting angiogenesis. These microRNAs are the first potential therapeutic target for kidney endothelial damage after AKI, and mimics may be broadly applicable to disease processes that involve endothelial injury.

Abstract

Background Damage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established.

Methods Antibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92endo−/−) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated.

Results miR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92endo−/− exacerbates renal IRI in male and female mice. Specifically, miR-17∼92endo−/− promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92endo−/− after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate.

Conclusions These data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.

  • microRNA
  • acute kidney injury
  • renal microvasculature
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (3)
Journal of the American Society of Nephrology
Vol. 32, Issue 3
March 2021
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Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury
Takuto Chiba, Débora M. Cerqueira, Yao Li, Andrew J. Bodnar, Elina Mukherjee, Katherine Pfister, Yu Leng Phua, Kai Shaikh, Brandon T. Sanders, Shelby L. Hemker, Patrick J. Pagano, Yijen L. Wu, Jacqueline Ho, Sunder Sims-Lucas
JASN Mar 2021, 32 (3) 553-562; DOI: 10.1681/ASN.2020050717

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Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury
Takuto Chiba, Débora M. Cerqueira, Yao Li, Andrew J. Bodnar, Elina Mukherjee, Katherine Pfister, Yu Leng Phua, Kai Shaikh, Brandon T. Sanders, Shelby L. Hemker, Patrick J. Pagano, Yijen L. Wu, Jacqueline Ho, Sunder Sims-Lucas
JASN Mar 2021, 32 (3) 553-562; DOI: 10.1681/ASN.2020050717
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