Functional differences between the susceptibility Z−2/C−106 and protective Z+2/T−106 promoter region polymorphisms of the aldose reductase gene may account for the association with diabetic microvascular complications

Yang, Bo; Millward, Ann; Demaine, A. G.

doi:10.1016/s0925-4439(03)00095-4

Cited by 33 publications

(33 citation statements)

References 23 publications

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“…Our previous study (24) found a highly significant difference in the luciferase activities between the recombinants that contain different AKR1B1 gene haplotypes that had been transfected into Hep G 2 cells exposed to high glucose. The present study confirmed that the Z-2/C-106 and Z/C-106 haplotypes have the highest transcription activities, and silencing of NFAT5 expression reduced the transcription activity of AKR1B1 even under high-glucose conditions.…”

Section: Discussionmentioning

confidence: 97%

“…SiRNA-569R or inv569R at 400 nmol/l or No-siRNA as controls was transfected into the HEK 293 cells. For analysis of AKR1B1 transcription, pGL3 reporter plasmids at 98 ng, which contain the promoter region with three OREs and different haplotypes of the AKR1B1 gene (24) and firefly luciferase gene downstream, were cotransfected with pRL-TK control plasmids at 2 ng, which contain the Renilla luciferase gene into the cells at 24 h after siRNA transfection. The next day, cells were divided into two groups: 1) cells maintained in original media and 2) cells switched to high-glucose conditions (31 mmol/l of D-glucose) for another 48 h or hypertonic conditions (extra 50 mmol/l NaCl) for another 20 h as positive controls.…”

Section: Methodsmentioning

confidence: 99%

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Elevated Activity of Transcription Factor Nuclear Factor of Activated T-Cells 5 (NFAT5) and Diabetic Nephropathy

et al. 2006

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The expression of aldose reductase is tightly regulated by the transcription factor tonicity response element binding protein (TonEBP/NFAT5) binding to three osmotic response elements (OREs; OREA, OREB, and OREC) in the gene. The aim was to investigate the contribution of NFAT5 to the pathogenesis of diabetic nephropathy. Peripheral blood mononuclear cells (PBMCs) were isolated from the following subjects: 44 Caucasoid patients with type 1 diabetes, of whom 26 had nephropathy and 18 had no nephropathy after a diabetes duration of 20 years, and 13 normal healthy control subjects. In addition, human mesangial cells (HMCs) were isolated from the normal lobe of 10 kidneys following radical nephrectomy for renal cell carcinoma. Nuclear and cytoplasmic proteins were extracted from PBMCs and HMCs and cultured in either normal or high-glucose (31 mmol/l D-glucose) conditions for 5 days. NFAT5 binding activity was quantitated using electrophoretic mobility shift assays for each of the OREs. Western blotting was used to measure aldose reductase and sorbitol dehydrogenase protein levels. There were significant fold increases in DNA binding activities of NFAT5 to OREB (2.06 ؎ 0.03 vs. 1.33 ؎ 0.18, P ‫؍‬ 0.033) and OREC (1.94 ؎ 0.21 vs. 1.39 ؎ 0.11, P ‫؍‬ 0.024) in PBMCs from patients with diabetic nephropathy compared with diabetic control subjects cultured under high glucose. Aldose reductase and sorbitol dehydrogenase protein levels in the patients with diabetic nephropathy were significantly increased in PBMCs cultured in high-glucose conditions. In HMCs cultured under high glucose, there were significant increases in NFAT5 binding activities to OREA, OREB, and OREC by 1.38 ؎ 0.22-, 1.84 ؎ 0.44-, and 2.38 ؎ 1.15-fold, respectively. Similar results were found in HMCs exposed to high glucose (aldose reductase 1.30 ؎ 0.06-fold and sorbitol dehydrogenease 1.54 ؎ 0.24-fold increases). Finally, the silencing of the NFAT5 gene in vitro reduced the expression of the aldose reductase gene. In conclusion, these results show that aldose reductase is upregulated by the transcriptional factor NFAT5 under high-glucose conditions in both PBMCs and HMCs.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Elevated Activity of Transcription Factor Nuclear Factor of Activated T-Cells 5 (NFAT5) and Diabetic Nephropathy

et al. 2006

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“…Polymorphism in the retinoid-X receptor (RXR) gamma gene has also been associated with DR (OR = 2.388; 95% confidence interval = 1.17-4.875) in Asians with T2D [126]. Polymorphisms in the regulatory region of the aldose reductase (ALR2) gene (encoding the rate-limiting enzyme of the polyol pathway) were associated with susceptibility to DN and DR [114,127]. However, the impacts of these genetic risk factors were modest, and some studies yielded inconsistent findings [128,129].…”

Section: Diabetic Retinopathymentioning

confidence: 99%

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

Murea

Ma²,

Freedman³

2012

Rev Diabet Stud

297

188

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Faced with a global epidemic of type 2 diabetes (T2D), it is critical that researchers improve our understanding of the pathogenesis of T2D and related vascular complications. These findings may ultimately lead to novel treatment options for disease prevention or delaying progression. Two major paradigms jointly underlie the development of T2D and related coronary artery disease, diabetic nephropathy, and diabetic retinopathy. These paradigms include the genetic risk variants and behavioral/environmental factors. This article systematically reviews the literature supporting genetic determinants in the pathogenesis of T2D and diabetic vasculopathy, and the functional implications of these gene variants on the regulation of beta-cell function and glucose homeostasis. We update the discovery of diabetes and diabetic vasculopathy risk variants, and describe the genetic technologies that have uncovered them. Also, genomic linkage between obesity and T2D is discussed. There is a complementary role for behavioral and environmental factors modulating the genetic susceptibility and diabetes risk. Epidemiological and clinical data demonstrating the effects of behavioral and novel environmental exposures on disease expression are reviewed. Finally, a succinct overview of recent landmark clinical trials addressing glycemic control and its impact on rates of vascular complications is presented. It is expected that novel strategies to exploit the gene-and exposure-related underpinnings of T2D will soon result.

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“…Animal species that are deficient in ALR2 gene expression in lens, such as the mouse, are relatively resistant to the onset of diabetic cataracts [25]. In contrast, genetic polymorphisms linked to the human AKR1B1 gene have been associated with higher tissue levels of ALR2 and development of more advanced diabetic retinopathy [20, 31]. …”

Section: Introductionmentioning

confidence: 99%

Aldose reductase-mediated induction of epithelium-to-mesenchymal transition (EMT) in lens

Zablocki

Ruzycki

Overturf

et al. 2011

Chemico-Biological Interactions

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Cataract is a key factor in the morbidity associated with diabetes. While the pathogenesis of diabetic cataract formation is poorly understood, previous research has identified aldose reductase (ALR2) as a key player. To elucidate a potential role for this enzyme in diabetic cataract formation, we created a series of transgenic mice designed for expression of human ALR2 (AKR1B1) in epithelial and outer cortical fiber cells of the lens. One of the founder lines, designated PAR39, developed an early onset cataract that involved formation of a plaque of cells at the anterior aspect of the lens. These cells appear to separate from the anterior epithelium and undergo a dramatic change that is reminiscent of the epithelial to mesenchymal transition (EMT). We characterized this phenotype in the PAR39 strain by examining rates of cell proliferation and by immunostaining for markers of EMT. Incorporation of the thymidine analog bromodeoxyuridine (BrdU) was used to estimate cell proliferation in two functional areas of the lens epithelium: the mitotically active germinative zone (GZ) and the less proliferative center zone (CZ). Staining cell nuclei with diamido 4',6-diamidino-2-phenylindole (DAPI) was used to establish a total cell count in the demarcated areas. Lens epithelium in PAR39 transgenic mice demonstrated a decrease in the percentage of BrdU/DAPI staining within the GZ as compared to nontransgenic littermate controls (8.1% vs. 10.9%). A similar decrease in BrdU/DAPI was observed in the CZ (0.6% compared to 3.3%). However, cell density was greater within the GZ of PAR39 mice as compared with nontransgenic controls, while it was not significantly different in the CZ among the two groups. Furthermore, cells associated with the epithelial plaque did not stain positive for BrdU, but were strongly positive for alpha-smooth muscle actin, a classical marker for EMT. These findings suggest that ALR2 over-expression is associated with an alteration in the balance between proliferation and apoptosis of epithelial cells in the mouse lens, and that cells associated with epithelial plaques in the PAR39 lens have features in common with cells undergoing EMT.

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Functional differences between the susceptibility Z−2/C−106 and protective Z+2/T−106 promoter region polymorphisms of the aldose reductase gene may account for the association with diabetic microvascular complications

Cited by 33 publications

References 23 publications

Elevated Activity of Transcription Factor Nuclear Factor of Activated T-Cells 5 (NFAT5) and Diabetic Nephropathy

Elevated Activity of Transcription Factor Nuclear Factor of Activated T-Cells 5 (NFAT5) and Diabetic Nephropathy

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

Aldose reductase-mediated induction of epithelium-to-mesenchymal transition (EMT) in lens

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