Polymorphisms of the UCP2 Gene Are Associated with Glomerular Filtration Rate in Type 2 Diabetic Patients and with Decreased UCP2 Gene Expression in Human Kidney

Abstract

IntroductionUncoupling protein 2 (UCP2) reduces production of reactive oxygen species (ROS) by mitochondria. ROS overproduction is one of the major contributors to the pathogenesis of chronic diabetic complications, such as diabetic kidney disease (DKD). Thus, deleterious polymorphisms in the UCP2 gene are candidate risk factors for DKD. In this study, we investigated whether UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms were associated with DKD in patients with type 2 diabetes mellitus (T2DM), and whether they had an effect on UCP2 gene expression in human kidney tissue biopsies.Materials and MethodsIn a case-control study, frequencies of the UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms as well as frequencies of the haplotypes constituted by them were analyzed in 287 T2DM patients with DKD and 281 T2DM patients without this complication. In a cross-sectional study, UCP2 gene expression was evaluated in 42 kidney biopsy samples stratified according to the presence of the UCP2 mutated -866A/55Val/Ins haplotype.ResultsIn the T2DM group, multivariate logistic regression analysis showed that the -866A/55Val/Ins haplotype was an independent risk factor for DKD (OR = 2.136, 95% CI 1.036–4.404), although neither genotype nor allele frequencies of the individual polymorphisms differed between case and control groups. Interestingly, T2DM patients carrying the mutated haplotype showed decreased estimated glomerular filtration rate (eGFR) when compared to subjects with the reference haplotype (adjusted P= 0.035). In kidney biopsy samples, UCP2 expression was significantly decreased in UCP2 mutated haplotype carriers when compared to kidneys from patients with the reference haplotype (0.32 ± 1.20 vs. 1.85 ± 1.16 n fold change; adjusted P< 0.000001).DiscussionData reported here suggest that the UCP2 -866A/55Val/Ins haplotype is associated with an increased risk for DKD and with a lower eGFR in T2DM patients. Furthermore, this mutated haplotype was associated with decreased UCP2 gene expression in human kidneys.

Mitochondrial energetics in the kidney

“…As ROS production contributes to mitochondrial dysfunction in AKI and diabetic nephropathy, UCP2 has been explored in the kidney and in these disease states 38 . Studies investigating the role of UCP2 polymorphisms in the kidney that exacerbate disease in patients with diabetic nephro pathy reveal that UCP2 is a potential target for treatment 39 . Lack of UCP2 has also been shown to worsen tubular injury after induction of experimental AKI in mice 38 .…”

-866G/A and Ins/Del polymorphisms in the UCP2 gene and diabetic kidney disease: case-control study and meta-analysis

“…Consistent with the role of UCP2 in decreasing oxidative stress, several studies have suggested that polymorphisms in the UCP2 gene are associated with ROS-related pathologies (Ji et al, 2004;Yu et al, 2009;Chai et al, 2012) and with the development of DM and its chronic complications (Jia et al, 2009;Crispim et al, 2010;de Souza et al, 2012de Souza et al, , 2013de Souza et al, , 2015. To date, three common UCP2 polymorphisms have been well studied: the functional -866G/A polymorphism (rs659366) in the promoter region; the Ala55Val polymorphism (rs660339) in exon 4, and the 45 bp insertion/deletion (Ins/Del) polymorphism in the 3' untranslated region (Jia et al, 2009;Dalgaard, 2011).…”

“…The -866G/A and the Ala55Val polymorphisms were in almost complete linkage disequilibrium in our population from the South of Brazil (Crispim et al, 2010). Recently, we reported that the polymorphic -866A/55Val/Ins haplotype was also an independent risk factor for DKD (OR = 2.14, 95% CI 1.04 -4.40) in patients with type 2 diabetes mellitus (T2DM) (de Souza et al, 2015). Moreover, T2DM patients carrying the polymorphic haplotype showed lower estimated GFR compared with patients carrying the reference haplotype (-866G/Ala55/Del).…”

“…Nevertheless, following careful analysis of their full texts, one article was excluded because it did not have a control group. Therefore, three articles (Lindholm et al, 2004;Tiwari et al, 2009;de Souza et al, 2015) plus the present case-control study were included in our meta-analysis, totalizing four articles (five studies). In total, 717 controls without DKD and 648 cases with this complication were analyzed for the -866G/A polymorphism, and 937 controls and 857 cases for the Ins/Del polymorphism.…”

“…Moreover, T2DM patients carrying the polymorphic haplotype showed lower estimated GFR compared with patients carrying the reference haplotype (-866G/Ala55/Del). Interestingly, the polymorphic haplotype was associated with decreased UCP2 gene expression in human kidney biopsy samples (de Souza et al, 2015).…”