title: Antagonism of profibrotic microRNA-21 improves outcome of murine chronic renal allograft dysfunction.
abstract: Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. It is characterized by interstitial fibrosis and tubular atrophy. The underlying pathomechanisms are incompletely understood. MicroRNAs are powerful regulators of gene expression and may have an impact on various diseases by direct mRNA decay or translational inhibition. A murine model of allogenic kidney transplantation was used resulting in CAD at 6 weeks after kidney transplantation. We identified fibrosis-associated miR-21a-5p by whole miRNAome expression analysis to be among the most highly upregulated miRNAs. In vitro in renal fibroblasts, miR-21a-5p was transcriptionally activated by interleukin 6-induced signal transducer and activator of transcription 3. Co-culture of LPS-activated macrophages with renal fibroblasts increased expression levels of miR-21a-5p and markers of fibrosis and inflammation. In addition, mature miR-21a-5p was secreted by macrophages in small vesicles, which were internalized by renal fibroblasts, thereby promoting profibrotic and proinflammatory effects. Notch2 receptor was identified as a potential target of miR-21a-5p and validated by luciferase gene reporter assays. Therapeutic silencing of miR-21a-5p in mice after allogenic kidney transplantation resulted in an amelioration of CAD, as indicated by a reduction in fibrosis development, inflammatory cell influx, tissue injury and BANFF lesion scoring. In a life-supporting model, miR-21a-5p antagonism had beneficial effects on kidney function. miR-21a-5p silencing may therefore be a viable therapeutic option in the treatment of patients following kidney transplantation to halt the development of CAD.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Celina
authors.initials: C
authors.lastname: Schauerte
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Hübner
authors.affiliation: Department of Nephrology, Hannover Medical School, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Pediatric Research Center (PFZ), Hannover Medical School, Germany.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Hannover Medical School, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.affiliation: Department of Laboratory Medicine & Pathology, University of Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Mengel
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Dettling
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bang
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Scherf
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Koelling
authors.affiliation: Pediatric Research Center (PFZ), Hannover Medical School, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.affiliation: Department of Nephrology, Hannover Medical School, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany; National Heart and Lung Institute, Imperial College London, UK. Electronic address: Thum.Thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany; Department of Nephrology, Hannover Medical School, Germany; University Hospital Zürich, Switzerland. Electronic address: Johan.Lorenzen@usz.ch.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Lorenzen
mesh_terms: D064591:Allografts / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts; D005355:Fibrosis; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000235:genetics*; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008264:Macrophages; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D009841:Oligonucleotides; D051883:Receptor, Notch2; C497765:Notch2 protein, mouse; C477371:locked nucleic acid; C531950:MIRN21 microRNA, mouse
keywords: IL-6; Notch2; chronic renal allograft dysfunction; microRNA-21