Association of the Arg72Pro Polymorphism in p53 with Progression of Diabetic Nephropathy in T2DM Subjects

Katerina Kankova

doi:10.4172/2161-0959.1000153

Abstract

Objective: In addition to its anticancer function, p53 (regulated by murine double minute 2 oncoprotein, MDM2) has recently been shown to control intracellular metabolic processes. It participates in the regulation of glucose, fatty and amino acid and purine metabolism, influences mitochondrial integrity and oxidative phosphorylation, insulin sensitivity, antioxidant response and autophagy. With respect to the possible impact of genetic variability in p53 and MDM2 on metabolic compensation the aim of the study was to analyse the effect of common germ line Single Nucleotide Polymorphisms (SNPs) - Arg72Pro in the TP53 and SNP309 in the MDM2 - on the progression of Diabetic Nephropathy (DN), cardiovascular morbidity and mortality and all-cause mortality in Type 2 Diabetes Mellitus (T2DM) subjects. Methods: The cross-sectional study comprised a total of 309 (a sum of 155 and 154) unrelated Caucasian diabetic patients with diabetes duration at least 10 years and variable renal function at baseline (309, mean age was 67.2 ± 10.8 years). The stage of diabetic nephropathy was defined according to the urinary albumin excretion and glomerular filtration rate. Patients were followed-up for median 37 (20-59) months. The following end-points were considered: (a) progression of DN, (b) major cardiovascular event (non-fatal or fatal myocardial infarction or stroke, limb amputation, revascularization), (c) all-cause mortality. Genotypes were determined by PCR-based methodology. Time-to-event analysis using Kaplan-Meier curves and log-rank test was used. Results: We found significant difference between CG+GG vs. CC genotypes of the p53 Arg72Pro SNP for DN progression (P=0.046, log-rank test). Carriers of genotypes containing G allele (previously associated with susceptibility to T2DM) had faster progression of DN than CC genotype carriers. We did not find any significant difference between genotypes of MDM2 SNP for any of the end-points studied. Conclusions: Presented findings in general support the role of p53 in the pathogenesis of metabolic diseases, namely progression of hyperglycemia-related morbidity. Nevertheless, further studies are warranted to elucidate the eventual causal involvement of p53 pathway in the development of diabetic complications.

Highlights

The physiological role of p53 protein in the prevention of cancer development through blocking cell cycle progression, regulating cellular senescence or apoptosis is well established [1]
Activation of Phosphate Pathway (PPP) is especially relevant in diabetes where it may have protective effect counteracting the negative consequences of hyperglycaemia
The baseline stage of Diabetic Nephropathy (DN) was defined according to the Urinary Albumin Excretion (UAE)

Summary

Introduction

The physiological role of p53 protein in the prevention of cancer development through blocking cell cycle progression, regulating cellular senescence or apoptosis is well established [1]. By regulating gene expression and other indirect means p53 participates in the regulation of glucose, fatty acid, amino acid (glutaminolysis) and purine metabolism, influences mitochondrial integrity and oxidative phosphorylation, insulin sensitivity, antioxidant response, autophagy and mammalian Target of Rapamycin (mTOR) signalling to name a few [3]. P53 induces expression of TP53-Induced Glycolysis And Apoptosis Regulator (TIGAR) which stimulates Pentose Phosphate Pathway (PPP) with subsequent production of reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) necessary for reduction of glutathione supporting an efficient antioxidant defence [4]. PPP can process glucose intermediates accumulating due to hyperglycaemia that activate metabolic pathways largely responsible for the development and progression of microvascular diabetic complications [5]

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Results

Conclusion