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

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 , which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R inj...

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Published in:Journal of the American Society of Nephrology 2021-02, Vol.32 (2), p.323-341
Main Authors: 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
Format: Article
Language:English
Subjects:
Acute Kidney Injury - etiology
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Adult
Animals
Basic Research
Cell Culture Techniques
Dependovirus
Disease Models, Animal
Endothelial Cells - metabolism
Endothelial Cells - pathology
Female
Humans
Ischemia - complications
Ischemia - metabolism
Ischemia - pathology
Male
Mice
MicroRNAs - metabolism
Middle Aged
RNA, Long Noncoding - metabolism
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Summary: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 , which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury. Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated . analyses used constitutive knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying caused overexpression in the kidney. Expression of in kidney transplant patients with I/R injury was investigated. is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1- , LHX8, and SPI1 activate in ECs and TECs. overexpression promotes angiogenesis and , transient AAV2-mediated 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. overexpression confers protection against renal injury by stimulating proangiogenic signaling. overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2020060775