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Basic Research
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Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p

George Haddad, Malte Kölling, Urs A. Wegmann, Angela Dettling, Harald Seeger, Roland Schmitt, Inga Soerensen-Zender, Hermann Haller, Andreas D. Kistler, Anne Dueck, Stefan Engelhardt, Thomas Thum, Thomas F. Mueller, Rudolf P. Wüthrich and Johan M. Lorenzen
JASN February 2021, 32 (2) 323-341; DOI: https://doi.org/10.1681/ASN.2020060775
George Haddad
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Malte Kölling
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Urs A. Wegmann
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Angela Dettling
2Department of Nephrology, Hannover Medical School, Hannover, Germany
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Harald Seeger
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Roland Schmitt
2Department of Nephrology, Hannover Medical School, Hannover, Germany
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Inga Soerensen-Zender
2Department of Nephrology, Hannover Medical School, Hannover, Germany
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Hermann Haller
2Department of Nephrology, Hannover Medical School, Hannover, Germany
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Andreas D. Kistler
3Department of Internal Medicine, Cantonal Hospital Frauenfeld, Frauenfeld, Switzerland
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Anne Dueck
4Institute of Pharmacology and Toxicology, Technical University of Munich, Munich, Germany
5German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany
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Stefan Engelhardt
4Institute of Pharmacology and Toxicology, Technical University of Munich, Munich, Germany
5German Center for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany
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Thomas Thum
6Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
7Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
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Thomas F. Mueller
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Rudolf P. Wüthrich
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Johan M. Lorenzen
1Department of Nephrology, University Hospital Zürich, Zurich, Switzerland
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Significance Statement

Renal ischemia-reperfusion injury is a major cause of AKI. The contribution of noncoding RNAs to this process is currently being explored. This study indicates that the long noncoding RNA H19 is silenced in adult mice and reactivated in ischemic AKI. Mechanistically, H19 functions as a competing endogenous RNA, ultimately activating important proangiogenic signaling pathways. Pharmacologic overexpression of H19 attenuates ischemic AKI by preserving capillary integrity. It may be used as a powerful therapeutic tool in the future care of patients with ischemic AKI.

Abstract

Background Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA H19, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury.

Methods Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated H19 in vitro. In vivo analyses used constitutive H19 knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying H19 caused overexpression in the kidney. Expression of H19 in kidney transplant patients with I/R injury was investigated.

Results H19 is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and ex vivo sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-α, LHX8, and SPI1 activate H19 in ECs and TECs. H19 overexpression promotes angiogenesis in vitro and in vivo. In vivo, transient AAV2-mediated H19 overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1.

Conclusions H19 overexpression confers protection against renal injury by stimulating proangiogenic signaling. H19 overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.

  • ischemic acute kidney injury
  • lncRNA
  • H19
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (2)
Journal of the American Society of Nephrology
Vol. 32, Issue 2
February 2021
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Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p
George Haddad, Malte Kölling, Urs A. Wegmann, Angela Dettling, Harald Seeger, Roland Schmitt, Inga Soerensen-Zender, Hermann Haller, Andreas D. Kistler, Anne Dueck, Stefan Engelhardt, Thomas Thum, Thomas F. Mueller, Rudolf P. Wüthrich, Johan M. Lorenzen
JASN Feb 2021, 32 (2) 323-341; DOI: 10.1681/ASN.2020060775

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Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p
George Haddad, Malte Kölling, Urs A. Wegmann, Angela Dettling, Harald Seeger, Roland Schmitt, Inga Soerensen-Zender, Hermann Haller, Andreas D. Kistler, Anne Dueck, Stefan Engelhardt, Thomas Thum, Thomas F. Mueller, Rudolf P. Wüthrich, Johan M. Lorenzen
JASN Feb 2021, 32 (2) 323-341; DOI: 10.1681/ASN.2020060775
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