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Author Notes:

E-mail: yunba@pcom.edu

Conceptualization: YB JLG. Data curation: YB. Formal analysis: CK. Funding acquisition: YB JLG. Investigation: YB. Methodology: YB JLG. Project administration: YB. Resources: PG. Software: CEF. Supervision: YB. Validation: CK CEF. Visualization: YB CEF. Writing – original draft: YB. Writing – review & editing: YB CEF.

Competing Interests: The authors have declared that no competing interests exist.

Subject:

Research Funding:

Philadelphia College of Osteopathic Medicine Chief Research and Science Officer (CRSO) Grant to Jennifer L. Gooch.

National Institutes of Health NIH1R15GM113120-01 to Yun Bai.

This work was supported by NIH grant 1R15GM113120-01 to YB and Philadelphia College of Osteopathic Medicine, Chief Research and Science Officer (CRSO) grant to YB.

Keywords:

  • Animals
  • Calcineurin Inhibitors
  • Cyclosporine
  • Gene Regulatory Networks
  • HEK293 Cells
  • Humans
  • Immunosuppressive Agents
  • Kidney
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs
  • RNA, Messenger
  • Transcriptome

Cyclosporine A alters expression of renal microRNAs: New insights into calcineurin inhibitor nephrotoxicity

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 12, Number 4

Publisher:

, Pages e0175242-e0175242

Type of Work:

Article | Final Publisher PDF

Abstract:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Calcineurin inhibitors are powerful immunosuppressants that revolutionized organ transplantation. However, non-immune effects of the calcineurin inhibitor, such as cyclosporine A (CsA), have significantly hindered their use. Specifically, nephrotoxicity, which is associated with tubulointerstitial fibrosis, inflammation, and podocyte damage, affects up to half of all transplant patients. Calcineurin is involved in many aspects of kidney development and function; therefore, mechanisms of CsA-induced nephrotoxicity are complex and not yet fully understood. MicroRNAs are short non-coding RNAs that regulate protein-coding RNA expression through post-translational repression of target messenger RNAs. MicroRNA dysregulation is known to be involved in kidney diseases including fibrosis. In this study, we compared the renal microRNA expression profiles between mice that received CsA (20 mg/ kg) or vehicle daily for six weeks. The results demonstrate that CsA induces significant changes in renal microRNA expression profile. We used combined criteria of False Discovery Rate (≤0.1), fold change (≥2) and median signal strength (≥50) and identified 76 differencially expressed microRNAs. This approach identified microRNAs previously linked to renal fibrosis that includes let-7d, miR-21, miR-29, miR-30, miR-130, miR-192, and miR-200 as well as microRNAs that have not been reported to be related to nephrotoxicity or immunosuppression. Pathway analysis of microRNA/mRNA changes highlights the Wnt, TGF-β, mTOR, and VEGF pathways. The mRNA expression profiles were compared in the same samples. The change of mRNA and microRNA profiles showed close correlations. To validate that the observed microRNA and mRNA expression level changes in mice kidney tissue were directly related to CsA treatment, the expression change induced by CsA treatment of three microRNAs (miR-21, miR-186, and miR-709) and three mRNAs (BMPR1a, SMURF1 and SMAD7) were compared in HEK293 cell line. A similar trend of expression level change was induced by CsA treatment in all selected microRNAs and mRNAs in the in vitro cell model. These data provide a roadmap for future work to study the role of the known and novel candidate microRNAs in the mechanism of nephrotoxicity and their further therapeutic potential.

Copyright information:

© 2017 Gooch et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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