Differentially Expressed Urinary Exo-miRs and Clinical Outcomes in Kidney Recipients on Short-Term Tacrolimus Therapy: A Pilot Study

Abstract

Aim: To analyze the expression of urinary exosome-derived miRNAs (exo-miRs) in kidney recipients on tacrolimus-based therapy. Patients&methods: Clinical and drug monitoring data were recorded from 23 kidney recipients. Expression of 93 exo-miRs was measured by quantitative PCR array and mRNA targets were explored. Results: 16 exo-miRs were differentially expressed, including marked upregulation of miR-155-5p, and downregulation of miR-223-3p and miR-1228-3p. Expression of miR-155-5p and miR-223-3p correlated with tacrolimus dose (p < 0.05), miR-223-3p with serum creatinine (p < 0.05), and miR-223-3p and miR-1228-3p with blood leukocytes (p < 0.05). 12 miRNAs have predicted targets involved in cell proliferation, apoptosis, stress response, PIK3/AKT/mTOR and TGF-β signaling pathways. Conclusion: Differentially expressed urinary exo-miRs may be useful markers to monitor tacrolimus therapy and graft function in kidney transplantation.

Keywords::

• kidney transplantation
• microRNA
• microRNA expression
• tacrolimus
• urinary exosomes

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0160

author-contributions

RDC Hirata, CR Felipe and H Tedesco-Silva Jr conceived and designed the research project. CR Felipe, H Tedesco-Silva Jr, JO Medina-Pestana, and V Bonezi obtained clinical and laboratory data. RC Costa de Freitas and RH Bortolin performed the experimental procedures and statistical analyzes. TDC Hirata performed the in silico study. RC Costa de Freitas, RH Bortolin and RDC Hirata wrote the manuscript. FDV Genvigir, CR Felipe, HT-S Jr, MH Hirata, A Cerda and SQ Doi critically reviewed the manuscript.

Acknowledgments

The authors thank N Oliveira, PC Salgado, CM Fajardo and ABC Salazar for the selection of patients and data collection. KC Rocha, AC Rodrigues, LM Bella, JO Martins, CZ Bueno and COR Yagui for technical support in exosome characterization.

Financial&competing interests disclosure

This work was supported by grants from FAPESP (#2016/13118-8), CNPq (#306061/2013-9) and CAPES (#Code 001), Brazil. V Bonezi was recipient of a fellowship from CAPES, Brazil. FDV Genvigir and PC Salgado were recipients of fellowships from FAPESP, Brazil. MH Hirata and RDC Hirata are recipients of fellowships from CNPq, Brazil. RC Costa de Freitas and RH Bortolin are recipients of fellowships from FAPESP, Brazil. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study protocol was approved by the ethics committees of the Federal University of Sao Paulo (UNIFESP, #054/2008) and School of Pharmaceutical Sciences of the University of Sao Paulo (FCF/USP, #517), Sao Paulo, Brazil. The study was conducted according to good clinical practices and the Declaration of Helsinki guidelines. All subjects signed an approved written informed consent before enrollment.

Additional information

Funding

This work was supported by grants from FAPESP (#2016/13118-8), CNPq (#306061/2013-9) and CAPES (#Code 001), Brazil. V Bonezi was recipient of a fellowship from CAPES, Brazil. FDV Genvigir and PC Salgado were recipients of fellowships from FAPESP, Brazil. MH Hirata and RDC Hirata are recipients of fellowships from CNPq, Brazil. RC Costa de Freitas and RH Bortolin are recipients of fellowships from FAPESP, Brazil. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.