Overexpression of BAX, NOL3, and XIAP Apoptotic Genes Participates in Calcineurin Inhibitors Nephrotoxicity: New Insights into Chronic Allograft Dysfunction

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Abstract

Introduction

Calcineurin inhibitors (CNI) remain the most effective and widely used immunosuppressive agents in organ transplantation, is a factor that limit the outcome of renal transplantation graft rejection. Renal biopsy remains the best method for identifying nephrotoxicity. The hypoxia causes histological data as nodular hyalinosis, hyalinosis, fibrosis, thrombotic microangiopathy, and isometric tubular vacuolization. The diagnosis requires an invasive procedure, an expert pathologist, but more importantly: it is an exclusion diagnosis.

Aim

Exploratory and descriptive study of the gene expression behavior of representative extrinsic and intrinsic apoptotic pathways in renal biopsies of 5 patients with CNIT where compare with biopsies without toxicity data.

Subjects and Methods

An Observational, descriptive cross sectional study was conducted. A convenience size of 7 renal biopsies samples was included from the Organ Transplant Unit of the Hospital General de México from January to March 2017. 5 correspond to transplanted patients with clinical, biochemical or histopathological data of calcineurin-inhibitors toxicity (CNIT). The mRNA expression of renal tissue biopsies was analyzed using the RT2 Profiler PCR Array platform considering genes involved processes associated with renal damage.

Results

Two of five patients presented acute renal dysfunction with clinical and biochemical data with creatinine values of 2.5 mg/dl and CNIT values before the biopsy of 16ng/ml and 21 mg/ml respectively. The rest of the cases the toxicity was an incidental finding in the year follow up biopsy during the histopathological analysis.

Results

The expression analyses of the genes associated directly with the inflammatory process (interleukins 2, 4, 6, 8, 10, TNF alpha, and TNF beta) showed in all the cases and also in the controls the absence of any detectable transcript in all the cytokines studied. Interesting was that in all the samples an undetectable value was obtained, not even basal expression compared with the constitutive gene. The QPCR arrays showed that Bcl-2-associated X protein (BAX), Nucleolar Protein 3 (NOL3) and X-Linked Inhibitor of Apoptosis (XIAP) were consistent only in the CNIT patients. The Mann-Whitney U test was consistent for the three evaluated genes revealed in the control group an average rank of 1.5, while the patients have three more times with respect the control. This result suggests that in the group of patients with CNIT BAX is activated, this gene is a key player in the intrinsic apoptosis pathway, suggesting that apoptosis via mitochondria is turn on probably due to the arteriolar vasoconstriction and the hypoxic state.

Conclusions

We proposed that intrinsic apoptotic pathway plays a relevant role in the physiopathology of the CNIT.

Conclusions

In representation of the work team I would like to state, that there are no known conflicts of interest associated with this work.

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