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Kidney Int. 2017 Sep;92(3):646-656. doi: 10.1016/j.kint.2017.02.012. Epub 2017 Apr 8.

Antagonism of profibrotic microRNA-21 improves outcome of murine chronic renal allograft dysfunction.

Author information

1
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany.
2
Department of Nephrology, Hannover Medical School, Germany.
3
Pediatric Research Center (PFZ), Hannover Medical School, Germany.
4
Department of Laboratory Medicine & Pathology, University of Alberta, Canada.
5
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.
6
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.

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.

KEYWORDS:

IL-6; Notch2; chronic renal allograft dysfunction; microRNA-21

PMID:
28396121
DOI:
10.1016/j.kint.2017.02.012
[Indexed for MEDLINE]

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