Abstract
Background: Antibody-mediated rejection (AMR) is the major cause of kidney transplant rejection. The donor-specific human leukocyte antigen (HLA) antibody (DSA) response to a renal allograft is not fully understood yet. mTOR complex has been described in the accommodation or rejection of transplants and integrates responses from a wide variety of signals. The aim of this study was to analyze the expression of the mTOR pathway genes in a large cohort of kidney transplant patients to determine its possible influence on the transplant outcome.Methods: A total of 269 kidney transplant patients monitored for DSA were studied. The patients were divided into two groups, one with recipients that had transplant rejection (+DSA/+AMR) and a second group of recipients without rejection (+DSA/–AMR and –DSA/–AMR, controls). Total RNA was extracted from kidney biopsies and reverse transcribed to cDNA. Human mTOR-PCR array technology was used to determine the expression of 84 mTOR pathway genes. STRING and REVIGO software were used to simulate gene to gene interaction and to assign a molecular function.Results: The studied groups showed a different expression of the mTOR pathway related genes. Recipients that had transplant rejection showed an over-expressed transcript (≥5-fold) of AKT1S1, DDIT4, EIF4E, HRAS, IGF1, INS, IRS1, PIK3CD, PIK3CG, PRKAG3, PRKCB (>12-fold), PRKCG, RPS6KA2, TELO2, ULK1, and VEGFC, compared with patients that did not have rejection. AKT1S1 transcripts were more expressed in +DSA/–AMR biopsies compared with +DSA/+AMR. The main molecular functions of up-regulated gene products were phosphotransferase activity, insulin-like grown factor receptor and ribonucleoside phosphate binding. The group of patients with transplant rejection also showed an under-expressed transcript (≥5-fold) of VEGFA (>15-fold), RPS6, and RHOA compared with the group without rejection. The molecular function of down-regulated gene products such as protein kinase activity and carbohydrate derivative binding proteins was also analyzed.Conclusions: We have found a higher number of over-expressed mTOR pathway genes than under-expressed ones in biopsies from rejected kidney transplants (+DSA/+AMR) with respect to controls. In addition to this, the molecular function of both types of transcripts (over/under expressed) is different. Therefore, further studies are needed to determine if variations in gene expression profiles can act as predictors of graft loss, and a better understanding of the mechanisms of action of the involved proteins would be necessary.
Highlights
Humoral rejection in renal transplantation is usually caused by the presence of preformed antibodies in the recipient against human leukocyte antigens (HLA) of the donor [1, 2], referred to as donor-specific antibodies (DSAs)
The mammalian target of rapamycin (mTOR) forms two structurally and functionally distinct complexes, called rapamycin-sensitive complex 1 mammalian target 1 and rapamycin-insensitive complex 2 mammalian target 2. mTORC1 consists of mTOR, raptor, GβL, and DEPTOR, while mTORC2 consists of mTOR, RICTOR, GβL, PRR5, and SIN1. mTORC1 combines signals from various growth factors, nutrients and energy supply to promote cell growth and regulates multiple biosynthetic cellular processes [17,18,19,20,21,22]. mTORC1 mainly regulates cell growth and metabolism, while mTORC2 controls cell proliferation and survival in particular [17, 20, 22]
No statistically significant differences were observed in mTOR pathway gene expression in recipients with no rejection with or without DSA (–DSA/–antibody-mediated rejection (AMR) and +DSA/–AMR; data not shown)
Summary
Humoral rejection in renal transplantation is usually caused by the presence of preformed antibodies in the recipient against human leukocyte antigens (HLA) of the donor [1, 2], referred to as donor-specific antibodies (DSAs). Antibodymediated rejection (AMR) is the major cause of kidney transplant rejection [3,4,5]. The influence of HLA matching and preformed DSAs in kidney transplantation remains unclear [11,12,13,14]. Antibody-mediated rejection (AMR) is the major cause of kidney transplant rejection. The donor-specific human leukocyte antigen (HLA) antibody (DSA) response to a renal allograft is not fully understood yet. The aim of this study was to analyze the expression of the mTOR pathway genes in a large cohort of kidney transplant patients to determine its possible influence on the transplant outcome
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