Isolation of the Mouse Aldose Reductase Promoter and Identification of a Tonicity-responsive Element

Daoudal, Sylviane; Tournaire, Colette; Halere, Alain; Veyssière, G.; Jean, C

doi:10.1074/jbc.272.5.2615

Cited by 40 publications

(20 citation statements)

References 36 publications

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“…34 Thus, the sensitivity of AR to oxidants appears to be a phylogenetically well conserved response and may be due to the presence of consensus sequences for binding of ROS-sensitive transcription factors such as nuclear factor-B and activator protein-1 in the promoter site of the gene. 35 Increased transcription of AR by tumor necrosis factor-␣ has been recently demonstrated to be mediated by nuclear factor-B. 33 Although the role of specific transcription factors in mitogenic stimulation of AR was not tested, our results are consistent with redox regulation of the AR gene and indicate that AR may be upregulated in part by ROS generated by growth factors.…”

Section: Discussionsupporting

confidence: 77%

Involvement of Aldose Reductase in Vascular Smooth Muscle Cell Growth and Lesion Formation After Arterial Injury

Ruef

Liu

Bode

et al. 2000

ATVB

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Abstract-Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an important feature of atherosclerosis, restenosis, and hypertension. Although multiple mediators of VSMC growth have been identified, few effective pharmacological tools have been developed to limit such growth. Recent evidence indicating an important role for oxidative stress in cell growth led us to investigate the potential role of aldose reductase (AR) in the proliferation of VSMCs. Because AR catalyzes the reduction of mitogenic aldehydes derived from lipid peroxidation, we hypothesized that it might be a potential regulator of redox changes that accompany VSMC growth. Herein we report several lines of evidence suggesting that AR facilitates/mediates VSMC growth. Stimulation of human aortic SMCs in culture with mitogenic concentrations of serum, thrombin, basic fibroblast growth factor, and the lipid peroxidation product 4-hydroxy-trans-2-nonenal (HNE) led to a 2-to 4-fold increase in the steady-state levels of AR mRNA, a 4-to 7-fold increase in AR protein, and a 2-to 3-fold increase in its catalytic activity. Inhibition of the enzyme by sorbinil or tolrestat diminished mitogen-induced DNA synthesis and cell proliferation. In parallel experiments, the extent of reduction of the glutathione conjugate of HNE to glutathionyl-1,4-dihydroxynonene in HNE-exposed VSMCs was decreased by serum starvation or sorbinil. Immunohistochemical staining of cross sections from balloon-injured rat carotid arteries showed increased expression of AR protein associated with the neointima. The media of injured or uninjured arteries demonstrated no significant staining. Compared with untreated animals, rats fed sorbinil (40 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) displayed a 51% and a 58% reduction in the ratio of neointima to the media at 10 and 21 days, respectively, after balloon injury. Taken together, these findings suggest that AR is upregulated during growth and that this upregulation facilitates growth by enhancing the metabolism of secondary products of reactive oxygen species. (VSMCs) is one of the key features of atherogenesis, restenosis, and hypertension. It is preceded by endothelial dysfunction due to cardiovascular risk factors or mechanical injury, resulting in the expression of several growth factors and cytokines that exert mitogenic effects on VSMCs. 1,2 Recent evidence suggests that reactive oxygen species (ROS) are essential mediators of cell signaling initiated by growth factors and cytokines. 3,4 Stimulation of VSMCs by growth factors such as platelet-derived growth factor, fibroblast growth factor (FGF), 5 and thrombin 6 enhances ROS generation, and cell growth in response to these mitogens is inhibited by antioxidant interventions. 5,6 Thus, oxidative stress, which represents a consequence and a cause of endothelial dysfunction, appears to be involved in mediating and sustaining abnormal VSMC growth during atherosclerosis and restenosis. 7,8 However, the mechanisms by which ROS mediate cell growth remain unclear.The cellular reactions of ROS are co...

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Section: Discussionsupporting

confidence: 77%

Involvement of Aldose Reductase in Vascular Smooth Muscle Cell Growth and Lesion Formation After Arterial Injury

Ruef

Liu

Bode

et al. 2000

ATVB

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“…We identified a consensus tonicity-responsive enhancer (TonE) (44) approximately 312 bp upstream from the transcription start site. The rat Sgk1 TonE (TGGAAAATCACC) (Figure 2A) is completely homologous with the murine and human aldose reductase osmoregulatory elements (13,45). We introduced a series of point mutations into the putative TonE in the Sgk1 promoter-driven luciferase reporter and transfected these into IMCD cells.…”

Section: Resultsmentioning

confidence: 99%

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

Chen¹,

Grigsby²,

Law³

et al. 2009

J. Clin. Invest.

199

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In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum-and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1 -/-mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. IntroductionPersistent hypertonicity, typically reflecting a high extracellular sodium concentration, stresses mammalian cells due to the ensuing osmotic efflux of water that shrinks the cells and concentrates their contents. Under most conditions, the concentration of extracellular sodium in mammals is controlled primarily through regulation of water metabolism. As extracellular sodium and plasma tonicity rise, the thirst mechanism is activated, and secretion of the neurohypophyseal hormone vasopressin into plasma increases. Vasopressin binds to its cognate receptors in the collecting duct of the kidney, resulting in increased water retention.Following short-term water restriction, several mammals demonstrate an acute increase in urinary sodium excretion that is independent of changes in water metabolism. This response, termed dehydration natriuresis (1-11), plays an important role in preventing further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. A similar natriuresis is seen following infusion of hypertonic saline (12). Investigations to date have suggested a role for central versus peripheral osmoreceptors and blood-borne versus neural effectors in contributing to dehydration-induced natriuresis; however, the precise mechanism(s) underlying this natriuresis remains undefined.

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“…Two putative ARE-like sequences, ARE1 and ARE2, are found adjacent to TonE and AP1 site in the 5'-flanking region of the AR gene (11,15,29,30). The arrangement of these elements is highly conserved among animal species, suggesting that this region is important for the regulation of AR gene expression.…”

Section: Introductionmentioning

confidence: 97%

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

Nishinaka

Yabe‐Nishimura

2005

J Pharmacol Sci

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Abstract. Transcription factor Nrf2 regulates gene expression of drug metabolizing enzymes such as glutathione S-transferase via the antioxidant response element, ARE. Aldose reductase (AR), a member of the aldo-keto reductase (AKR) superfamily, metabolizes various endogenous and exogenous aldehydes. The AR gene 5'-flanking region contains a multiple stress response region (MSRR) composed of two putative AREs (ARE1 and ARE2), an AP1 site, and a tonicity response element (TonE). As this region is highly conserved among species, we examined the involvement of Nrf2 in transcriptional regulation of the AR gene. b-Naphthoflavone, an Nrf2 activator, elevated the level of AR mRNA in HepG2 cells and increased the promoter activity of the mouse AR (AKR1B3) gene. The promoter activity of the AKR1B3 gene, containing MSRR, was also augmented by overexpression of Nrf2. Deletion and mutation analyses indicated that both ARE1 and the AP1 site were essential for the responsiveness to Nrf2, while ARE2 was nonfunctional. The presence of an ARE1 binding protein complex was revealed by electrophoretic mobility shift assay. These findings indicate that Nrf2 regulates the AKR1B3 promoter activity via ARE1 and the AP1 site.

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Isolation of the Mouse Aldose Reductase Promoter and Identification of a Tonicity-responsive Element

Cited by 40 publications

References 36 publications

Involvement of Aldose Reductase in Vascular Smooth Muscle Cell Growth and Lesion Formation After Arterial Injury

Involvement of Aldose Reductase in Vascular Smooth Muscle Cell Growth and Lesion Formation After Arterial Injury

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

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

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