title: Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver.
abstract: microRNAs are an abundant class of small non-coding RNAs that negatively regulate gene expression. Importantly, microRNA activity has been linked to the control of cellular stress response. In the present study, we investigated whether the expression of hepatic microRNAs is affected by changes in ambient osmolarity. It is shown that hyperosmotic exposure of perfused rat liver induces a rapid upregulation of miR-15a, miR-15b and miR-16, which are members of the miR-15/107 microRNAs superfamily. It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs. Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs. It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Santosa
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Castoldi
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Martha
authors.initials: M
authors.lastname: Paluschinski
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Sommerfeld
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D001596:Benzylamines / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009994:Osmolar Concentration; D064587:Osmoregulation / Q000235:genetics; D009995:Osmosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D013312:Stress, Physiological / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000873:Anthracenes; D001596:Benzylamines; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C499515:FOXO3 protein, rat; C491898:Fas protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C547573:MIRN16 microRNA, rat; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019014:fas Receptor; C534110:mirn15 microRNA, rat; C432165:pyrazolanthrone; C030796:benzylamine; C056165:acetovanillone; D048031:JNK Mitogen-Activated Protein Kinases; D000111:Acetylcysteine