MicroRNA-24 antagonism prevents renal ischemia reperfusion injury

• Published in: Journal of the American Society of Nephrology 2014-12, Vol.25 (12), p.2717-2729
• Main Authors: Lorenzen, Johan M, Kaucsar, Tamas, Schauerte, Celina, Schmitt, Roland, Rong, Song, Hübner, Anika, Scherf, Kristian, Fiedler, Jan, Martino, Filippo, Kumarswamy, Regalla, Kölling, Malte, Sörensen, Inga, Hinz, Hebke, Heineke, Joerg, van Rooij, Eva, Haller, Hermann, Thum, Thomas
• Format: Article
• Language: English
• Subjects: Adult; Animals; Apoptosis; Basic Research; Binding Sites; Endothelial Cells - cytology; Endothelium - pathology; Epithelial Cells - metabolism; Female; Gene Silencing; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1 - metabolism; Histones - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Inflammation - metabolism; Kidney - metabolism; Kidney - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Male; Mice; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; Middle Aged; Receptors, Lysosphingolipid - metabolism; Reperfusion Injury - pathology
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2013121329

Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. MicroRNAs (miRs) are powerful regulators of various diseases. We investigated the role of apoptosis-associated miR-24 in renal I/R injury. miR-24 was upregulated in the kidney after I/R injury of mice and in patients after kidney transplantation. Cell-sorting experiments revealed a specific miR-24 enrichment in renal endothelial and tubular epithelial cells after I/R induction. In vitro, anoxia/hypoxia induced an enrichment of miR-24 in endothelial and tubular epithelial cells. Transient overexpression of miR-24 alone induced apoptosis and altered functional parameters in these cells, whereas silencing of miR-24 ameliorated apoptotic responses and rescued functional parameters in hypoxic conditions. miR-24 effects were mediated through regulation of H2A histone family, member X, and heme oxygenase 1, which were experimentally validated as direct miR-24 targets through luciferase reporter assays. In vitro, adenoviral overexpression of miR-24 targets lacking miR-24 binding sites along with miR-24 precursors rescued various functional parameters in endothelial and tubular epithelial cells. In vivo, silencing of miR-24 in mice before I/R injury resulted in a significant improvement in survival and kidney function, a reduction of apoptosis, improved histologic tubular epithelial injury, and less infiltration of inflammatory cells. miR-24 also regulated heme oxygenase 1 and H2A histone family, member X, in vivo. Overall, these results indicate miR-24 promotes renal ischemic injury by stimulating apoptosis in endothelial and tubular epithelial cell. Therefore, miR-24 inhibition may be a promising future therapeutic option in the treatment of patients with ischemic AKI.