Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Chen, Xiaolei; Tang, Wanxin; Tang, Xiaohong; Qin, Wei; Gong, Meng

doi:10.3109/0886022x.2014.930650

Cited by 24 publications

(18 citation statements)

References 30 publications

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“…This indicates that mitochondrial uncoupling was occurring in the db/db mice. As we also observed an up-regulation of Ucp-2 gene expression, our data are consistent with this model and other studies demonstrating the protective nature of Ucp-2 from oxidative stress [76,77].…”

Section: Discussionsupporting

confidence: 93%

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

et al. 2020

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Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif −/− ) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif −/− mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif −/− as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H 2 O 2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.

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Section: Discussionsupporting

confidence: 93%

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

et al. 2020

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“…Thereby, T2DM patients carrying the mutated UCP2 haplotype could have an increased risk for DKD development since UCP2 concentration in their kidneys might not be enough to compensate the oxidative stress produced by chronic hyperglycemia. In agreement with our hypothesis, a recent study showed that genipin, an UCP2 inhibitor, dramatically boosted oxidative stress in rat renal proximal tubular cells incubated with high glucose concentrations, and this exacerbated cellular apoptosis due to an increase in caspase-3 activation [ 48 ]. In addition, He et al .…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2015

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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.

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“…Moreover, UCP2 knockdown in NRK-52E tubular cells abolished the effect of TGF-b1 treatment, decreasing extracellular matrix production (Jiang et al, 2013). In contrast, Chen et al (2014) demonstrated that inhibition of UCP2 by genipin increased oxidative stress in rat proximal tubular cells treated with high glucose medium, and this led to increased cell apoptosis. UCP2 knockdown in renal mesangial cells of rats also increased oxidative stress, inflam-mation, and apoptosis in vitro (Di Castro et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2020

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Uncoupling protein 2 (UCP2) decreases reactive oxygen species (ROS). ROS overproduction is a key contributor to the pathogenesis of diabetic kidney disease (DKD). Thus, UCP2 polymorphisms are candidate risk factors for DKD; however, their associations with this complication are still inconclusive. Here, we describe a case-control study and a meta-analysis conducted to investigate the association between UCP2-866G/A and Ins/Del polymorphisms and DKD. The case-control study comprised 385 patients with type 1 diabetes mellitus (T1DM): 223 patients without DKD and 162 with DKD. UCP2-866G/A (rs659366) and Ins/Del polymorphisms were genotyped by real-time PCR and conventional PCR, respectively. For the meta-analysis, a literature search was conducted to identify all studies that investigated associations between UCP2 polymorphisms and DKD in patients with T1DM or type 2 diabetes mellitus. Pooled odds ratios were calculated for different inheritance models. Allele and genotype frequencies of-866G/A and Ins/Del polymorphisms did not differ between T1DM case and control groups. Haplotype frequencies were also similar between groups. Four studies plus the present one were eligible for inclusion in the meta-analysis. In agreement with case-control data, the meta-analysis results showed that the-866G/A and Ins/Del polymorphisms were not associated with DKD. In conclusion, our case-control and meta-analysis studies did not indicate an association between the analyzed UCP2 polymorphisms and DKD.

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Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Cited by 24 publications

References 30 publications

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D

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

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

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