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Haddad, George; Kölling, Malte; Wegmann, Urs A.; Dettling, Angela; Seeger, Harald; Schmitt, Roland; Soerensen-Zender, Inga; Haller, Hermann; Kistler, Andreas D.; Dueck, Anne; Engelhardt, Stefan; Thum, Thomas; Mueller, Thomas F.; Wüthrich, Rudolf P.; Lorenzen, Johan M.

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

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  • Media type: E-Article
  • Title: Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p
  • Contributor: Haddad, George; Kölling, Malte; Wegmann, Urs A.; Dettling, Angela; Seeger, Harald; Schmitt, Roland; Soerensen-Zender, Inga; Haller, Hermann; Kistler, Andreas D.; Dueck, Anne; Engelhardt, Stefan; Thum, Thomas; Mueller, Thomas F.; Wüthrich, Rudolf P.; Lorenzen, Johan M.
  • imprint: Ovid Technologies (Wolters Kluwer Health), 2021
  • Published in: Journal of the American Society of Nephrology
  • Language: English
  • DOI: 10.1681/asn.2020060775
  • ISSN: 1046-6673; 1533-3450
  • Keywords: Nephrology ; General Medicine
  • Origination:
  • Footnote:
  • Description: <jats:sec> <jats:title>Background</jats:title> <jats:p>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 <jats:italic toggle="yes">H19</jats:italic>, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated <jats:italic toggle="yes">H19 in vitro</jats:italic>. <jats:italic toggle="yes">In vivo</jats:italic> analyses used constitutive <jats:italic toggle="yes">H19</jats:italic> knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying <jats:italic toggle="yes">H19</jats:italic> caused overexpression in the kidney. Expression of <jats:italic toggle="yes">H19</jats:italic> in kidney transplant patients with I/R injury was investigated.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> <jats:italic toggle="yes">H19</jats:italic> is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and <jats:italic toggle="yes">ex vivo</jats:italic> sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-<jats:italic toggle="yes">α</jats:italic>, LHX8, and SPI1 activate <jats:italic toggle="yes">H19</jats:italic> in ECs and TECs. <jats:italic toggle="yes">H19</jats:italic> overexpression promotes angiogenesis <jats:italic toggle="yes">in vitro</jats:italic> and <jats:italic toggle="yes">in vivo. In vivo</jats:italic>, transient AAV2-mediated <jats:italic toggle="yes">H19</jats:italic> 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p> <jats:italic toggle="yes">H19</jats:italic> overexpression confers protection against renal injury by stimulating proangiogenic signaling. <jats:italic toggle="yes">H19</jats:italic> overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.</jats:p> </jats:sec>
  • Access State: Open Access