Differential expression of genes related to calcineurin and mTOR signaling and regulatory miRNAs in peripheral blood from kidney recipients under tacrolimus-based therapy

Vivian Bonezi; Fabiana Dalla Vecchia Genvigir; Patrícia de Cássia Salgado; Claudia Rosso Felipe; Helio Tedesco-Silva Jr; José Osmar Medina-Pestana; Alvaro Cerda; Sonia Quateli Doi; Mario Hiroyuki Hirata; Rosario Dominguez Crespo Hirata

doi:10.21037/atm-20-1757

Differential expression of genes related to calcineurin and mTOR signaling and regulatory miRNAs in peripheral blood from kidney recipients under tacrolimus-based therapy

Ann Transl Med. 2020 Sep;8(17):1051. doi: 10.21037/atm-20-1757.

Affiliations

¹ Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
² Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
³ Department of Basic Sciences, Center of Excellence in Translational Medicine, BIOREN, Universidad de La Frontera, Temuco, Chile.
⁴ School of Medicine, Uniformed Services University, Bethesda, MD, USA.

Abstract

Background: Genetic and epigenetics factors have been implicated in drug response, graft function and rejection in solid organ transplantation. Differential expression of genes involved in calcineurin and mTOR signaling pathway and regulatory miRNAs was analyzed in the peripheral blood of kidney recipient cohort (n=36) under tacrolimus-based therapy.

Methods: PPP3CA, PPP3CB, MTOR, FKBP1A, FKBP1B and FKBP5 mRNA expression and polymorphisms in PPP3CA and MTOR were analyzed by qPCR. Expression of miRNAs targeting PPP3CA (miR-30a, miR-145), PPP3CB (miR-10b), MTOR (miR-99a, miR-100), and FKBP1A (miR-103a) was measured by qPCR array.

Results: PPP3CA and MTOR mRNA levels were reduced in the first three months of treatment compared to pre-transplant (P<0.05). PPP3CB, FKBP1A, FKBP1B, and FKBP5 expression was not changed. In the 3^rd month of treatment, the expression of miR-99a, which targets MTOR, increased compared to pre-transplant (P<0.05). PPP3CA c.249G>A (GG genotype) and MTOR c.2997C>T (TT genotype) were associated with reduced expression of PPP3CA mRNA and MTOR, respectively. FKBP1B mRNA levels were higher in patients with acute rejection (P=0.026).

Conclusions: The expression of PPP3CA, MTOR and miR-99a in the peripheral blood of renal recipients is influenced by tacrolimus-based therapy and by PPP3CA and MTOR variants. These molecules can be potential biomarkers for pharmacotherapy monitoring.

Keywords: Circulating miRNAs; gene expression; kidney transplant; pharmacogenomics.