Transcription Factor Nrf2 Regulates Promoter Activity of Mouse Aldose Reductase (AKR1B3) Gene

Nishinaka, Toru; Yabe‐Nishimura, Chihiro

doi:10.1254/jphs.fp0040404

Cited by 65 publications

(29 citation statements)

References 37 publications

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“…Recently, we also observed increased expression of an anti-oxidative enzyme, glutathione peroxidase-3, in the cardiac ventricles of STZ-induced diabetic mice under the same experimental conditions (45). As expression of the AR gene is regulated by the cellular redox state via the transcription factor Nrf2 (25,46,47), the level of AR mRNA may be down-regulated by transient increase in GSH along with augmented activity of anti-oxidative enzymes at the early stage of hyperglycemia.…”

Section: Discussionmentioning

confidence: 79%

The Activity of Aldose Reductase Is Elevated in Diabetic Mouse Heart

et al. 2007

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Abstract. The importance of aldose reductase (AR) has been implicated in the pathogenesis of diabetic complications, although the alterations in the expression and activity of AR during hyperglycemia in the heart have not been well characterized. We investigated the expression and enzyme activity of AR in a murine diabetic model. Three weeks after the induction of hyperglycemia with streptozotocin, the level of AR mRNA was significantly reduced in the cardiac ventricles of BDF-1 mice. In contrast, the activity of AR was significantly elevated in the heart without any significant change in the protein level. In these mice, the level of cardiac thiobarbituric acid-reactive substances was unaltered, whereas the level of reduced glutathione (GSH) was significantly increased. Daily administration of insulin for 3 weeks completely normalized the level of AR mRNA and the enzyme activity. On the other hand, daily administration of an antioxidant, N-acetylcysteine significantly reduced the level of AR mRNA in the heart with a concomitant elevation in the enzyme activity. These results suggest that the activity of AR in the heart is affected by GSH dynamics. Augmented AR activity at the early stage of hyperglycemia may perturb glycolysis and affect cardiac performance.

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Section: Discussionmentioning

confidence: 79%

The Activity of Aldose Reductase Is Elevated in Diabetic Mouse Heart

et al. 2007

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“…In detailed studies in the murine aldose reductase Akr1b3, two adjacent AREs and an AP-1 site were required for maximal response to cotransfected Nrf2 (Nishinaka and Yabe-Nishimura, 2005). Potential AREs were also identified by sequence analysis in the proximal promoter region of Akr7a3, but they were not characterized (Ellis et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Lou

Du²,

Ji³

et al. 2006

Mol Pharmacol

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AKR1C2, also referred to as the human bile acid binder and 3␣-hydroxysteroid dehydrogenase type III, is a multifunctional oxidoreductase able to stereoselectively reduce steroids as well as oxidize or reduce polyaromatic hydrocarbons. Previously, this same protein was also identified by its robust induction by phase II inducers in HT29 cells. In HepG2 cells, both AKR1C2 and AKR1C1 (97% sequence homology) were induced by phase II inducers but not the highly related AKR1C3 and AKR1C4 family members (84% sequence homology). We now report the initial characterization of the proximal promoter of AKR1C2 in HepG2 cell line and the identification of a potent enhancer-like element responsive to phase II inducers located approximately 5.5 kilobases upstream from the transcription start site. DNA sequence analysis of this enhancer element revealed that it contained a consensus antioxidant response element (ARE), which was confirmed by mutation analysis.Treatment with phase II inducers leads to increased accumulation of nuclear factor-erythroid 2 p45-related factor (NRF) 2 in the nucleus, which was associated with increased binding to this ARE as determined by electrophoretic mobility shift assay. Transient transfection with Nrf2 increased the transcriptional activity of the ARE of AKR1C2 comparable with that observed with phase II inducers. Chromatin immunoprecipitation (ChIP) analysis also confirmed increased NRF2 binding to the ARE after induction by a phase II inducer. The AKR1C1 promoter also harbored this same ARE element in a highly homologous region, which was also bound by NRF2 in a ChiP analysis. No induction of the ARE of AKR1C2 was detected in Nrf2fibroblasts. The regulation of AKR1C2 by this distal ARE suggests that AKR1C2 detoxifies products of reactive oxidant injury, which has important implications for both hormone and xenobiotic metabolism.

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“…Aldose reductase is known as a target gene of Nrf2. 28,29) However, it seems unlikely that aldose reductase is induced by EPS because our previous study indicated that the reductase activity in Schwann cells was decreased by 30-50% after treatment with 10-100 µM EPS. 10) In addition, these findings suggest that the inhibition of aldose reductase does not contribute to the ability of EPS to increase HO-1 levels by activating Nrf2.…”

Section: )mentioning

confidence: 99%

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases. Key words epalrestat; heme oxygenase (HO)-1; superoxide dismutase (SOD); catalaseHeme oxygenase (HO)-1 is a stress-responsive enzyme that has anti-inflammatory, antioxidant, and cytoprotective functions. Expectations are high that the regulation and amplification of HO-1 by pharmacological approaches would lead to the discovery of novel drugs for the treatment of a variety of diseases.1) HO-1 has emerged as an anti-inflammatory therapeutic target.2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported.3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.3) However, such metalloporphyrins as cobalt protoporphyrin IX, which are prototypical inducers of HO-1 and commonly used in experimental cell culture and animal models, are not applicable to clinical interventions because of their high toxicity.2) It is expected that the upregulation of HO-1 by currently available pharmacological agents, whose safety and pharmacokinetics have already been confirmed clinically, would be useful for the treatment of a variety of diseases.The biochemical activities of heme degradation products and their metabolic derivatives contribute to the cytoprotective function of HO-1. HO-1 catalyzes the degradation of heme to produce ferrous iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted into bilirubin. Carbon monoxide is involved in inflammation regulation.4) Bilirubin and biliverdin, which can scavenge peroxyl radicals, are cytoprotec...

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Transcription Factor Nrf2 Regulates Promoter Activity of Mouse Aldose Reductase (AKR1B3) Gene

Cited by 65 publications

References 37 publications

The Activity of Aldose Reductase Is Elevated in Diabetic Mouse Heart

The Activity of Aldose Reductase Is Elevated in Diabetic Mouse Heart

Induction ofAKR1C2by Phase II Inducers: Identification of a Distal Consensus Antioxidant Response Element Regulated by NRF2

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

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