MicroRNA-24 antagonism prevents renal ischemia reperfusion injury.
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.
Institute of Molecular and Translational Therapeutic Strategies, Department of Nephrology, and.
Johan M
JM
Lorenzen
Institute of Molecular and Translational Therapeutic Strategies, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary;
Tamas
T
Kaucsar
Institute of Molecular and Translational Therapeutic Strategies.
Celina
C
Schauerte
Department of Nephrology, and.
Roland
R
Schmitt
Department of Nephrology, and.
Song
S
Rong
Institute of Molecular and Translational Therapeutic Strategies.
Anika
A
Hübner
Institute of Molecular and Translational Therapeutic Strategies.
Kristian
K
Scherf
Institute of Molecular and Translational Therapeutic Strategies.
Jan
J
Fiedler
Institute of Molecular and Translational Therapeutic Strategies.
Filippo
F
Martino
Institute of Molecular and Translational Therapeutic Strategies.
Regalla
R
Kumarswamy
Institute of Molecular and Translational Therapeutic Strategies.
Malte
M
Kölling
Department of Nephrology, and.
Inga
I
Sörensen
Department of Cardiology and Angiology, Hannover Medical School, Hannover Germany;
Hebke
H
Hinz
Department of Cardiology and Angiology, Hannover Medical School, Hannover Germany;
Joerg
J
Heineke
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, and University Medical Center Utrecht, Utrecht, The Netherlands; and.
Eva
E
van Rooij
Department of Nephrology, and.
Hermann
H
Haller
Institute of Molecular and Translational Therapeutic Strategies, National Heart and Lung Institute, Imperial College London, London, United Kingdom. Lorenzen.Johan@mh-hannover.de Thum.Thomas@mh-hannover.de.
Thomas
T
Thum
D000328:Adult; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D042783:Endothelial Cells / Q000166:cytology; D004727:Endothelium / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology*; D000081025:Sphingosine-1-Phosphate Receptors
D006657:Histones; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1
acute renal failure; apoptosis; endothelium; heme oxygenase; ischemia-reperfusion; proximal tubule