Urinary miR-16 transactivated by C/EBPβ reduces kidney function after ischemia/reperfusion-induced injury.
Ischemia-reperfusion (I/R) induced acute kidney injury (AKI) is regulated by transcriptional factors and microRNAs (miRs). However, modulation of miRs by transcriptional factors has not been characterized in AKI. Here, we found that urinary miR-16 was 100-fold higher in AKI patients. MiR-16 was detected earlier than creatinine in mouse after I/R. Using TargetScan, the 3'UTR of B-cell lymphoma 2 (BCL-2) was found complementary to miR-16 to decrease the fluorescent reporter activity. Overexpression of miR-16 in mice significantly attenuated renal function and increased TUNEL activity in epithelium tubule cells. The CCAAT enhancer binding protein beta (C/EBP-β) increased the expression of miR-16 after I/R injury. The ChIP and luciferase promoter assay indicated that about -1.0 kb to -0.5 kb upstream of miR-16 genome promoter region containing C/EBP-β binding motif transcriptionally regulated miR-16 expression. Meanwhile, the level of pri-miR-16 was higher in mice infected with lentivirus containing C/EBP-β compared with wild-type (WT) mice and overexpression of C/EBP-β in the kidney of WT mice reduced kidney function, increased kidney apoptosis, and elevated urinary miR-16 level. Our results indicated that miR-16 was transactivated by C/EBP-β resulting in aggravated I/R induced AKI and that urinary miR-16 may serve as a potential biomarker for AKI.
Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
Hsi-Hsien
HH
Chen
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Yi-Fan
YF
Lan
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Hsiao-Fen
HF
Li
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Department of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
Ching-Feng
CF
Cheng
Department of Emergency Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
Pei-Fang
PF
Lai
Division of Pathology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Wei-Hua
WH
Li
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Heng
H
Lin
D058186:Acute Kidney Injury / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D003404:Creatinine / Q000652:urine; D004848:Epithelium / Q000502:physiology; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000652:urine; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D005819:Genetic Markers; D035683:MicroRNAs; C522604:Mirn16 microRNA, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D003404:Creatinine