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. 2020 Sep;8(17):1051.
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

Vivian Bonezi  1 , Fabiana Dalla Vecchia Genvigir  1 , Patrícia de Cássia Salgado  1 , Claudia Rosso Felipe  2 , Helio Tedesco-Silva Jr  2 , José Osmar Medina-Pestana  2 , Alvaro Cerda  3 , Sonia Quateli Doi  4 , Mario Hiroyuki Hirata  1 , Rosario Dominguez Crespo Hirata  1
Affiliations

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 et al. Ann Transl Med. 2020 Sep.

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 3rd 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.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1757). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Expression of genes in peripheral blood of kidney recipients (n=36). The mRNA expression was measured by qPCR and normalized with UBC and B2M. The relative mRNA expression was calculated by 2-ΔCT formula. Box plots with median and the minimum and maximum values. Data compared by Kruskal-Wallis test and Dunn’s test for multiple comparisons. PreTx, pre-transplant.
Figure 2
Figure 2
Expression of miRNAs in peripheral blood of kidney recipients (n=22*). The miRNA expression was measured by qPCR array and normalized with RNU6-2, SNORD61, SNORD68, and SNORD95. The relative miRNA expression was calculated by 2-ΔCT formula. Box plots with median and the minimum and maximum values. Data compared by Kruskal-Wallis test and Dunn’s test for multiple comparisons. PreTx, pre-transplant. *, only 22 individuals had no missing data in evaluated times.
Figure 3
Figure 3
Association of PPP3CA and MTOR polymorphisms with mRNA expression in peripheral blood of kidney recipients (n=36). The mRNA expression was measured by qPCR and normalized with UBC and B2M. The relative mRNA expression was calculated by 2-ΔCT formula. Box plots with median and the minimum and maximum values. Data compared by Mann-Whitney U test and Kruskal-Wallis test and Dunn’s test for multiple comparisons. PreTx, pre-transplant.
Figure S1
Figure S1
Relationship of PPP3CA and MTOR mRNA expression and acute rejection of kidney recipients. The mRNA expression was measured by qPCR and normalized with UBC and B2M. The relative mRNA expression was calculated by 2-ΔCT formula. The data are shown as mean ± SEM. BCAR, biopsy confirming acute rejection; PreTx, pre-transplant.
See this image and copyright information in PMC

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