title: Role of microRNA-29b in the ochratoxin A-induced enhanced collagen formation in human kidney cells.
abstract: Ochratoxin A (OTA) is an ubiquitous mycotoxin suspected to cause fibrotic kidney diseases. The involvement of mircoRNAs in these processes is unknown. Here, we investigated the role of the anti-fibrotic miR-29b in OTA-induced alterations of cellular collagen homeostasis. OTA exposure of human embryonic kidney cells (HEK293) cells led to an increase of collagen I, III and IV protein amounts without changes in collagen mRNA expression levels, indicating post-transcriptionally mediated mechanisms potentially involving microRNAs and 3'UTRs of collagen mRNAs. This was confirmed by enhanced luciferase activity of a collagen1A1-3'UTR reporter plasmid after OTA exposure. OTA also enhanced the luciferase activity of a reporter plasmid containing the seed region of miR-29b showing that OTA diminishes miR-29b action. Additionally, OTA induced an altered intracellular distribution of miR-29b leading to decreased cytoplasmic abundance of miR-29b. Abundantly added miR-29b (miR-29b clamp) completely prevented OTA-induced collagen formation. In summary, we show that OTA has the potential to initiate or support the development of fibrotic kidney diseases by involving post-transcriptional regulation mechanisms comprising miR-29b. OTA reduces the impact of miR-29b and thus enhances collagen protein expression. These findings allow a new perspective on how the exposure to nanomolar OTA concentrations can lead to fibrotic tissue alterations.
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Straße 6, 06112 Halle (Saale), Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Hennemeier
authors.affiliation: Institut für Lebensmittelchemie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Humpf
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Straße 6, 06112 Halle (Saale), Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Straße 6, 06112 Halle (Saale), Germany. Electronic address: gerald.schwerdt@medizin.uni-halle.de.
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwerdt
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005355:Fibrosis; D017930:Genes, Reporter; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D009793:Ochratoxins / Q000633:toxicity*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D009793:Ochratoxins; D012333:RNA, Messenger; C025589:ochratoxin A
keywords: Collagens; Fibrosis; Kidney; Ochratoxin A; miRNA-29b