Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2

Alam, Jawed; Killeen, Erin; Gong, Peng; Naquin, Ryan; Hu, Bin; Stewart, Daniel P.; Ingelfinger, Julie R.; Nath, Karl A.

doi:10.1152/ajprenal.00376.2002

Cited by 154 publications

(108 citation statements)

References 51 publications

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“…It has been shown that activation of the ERK pathway may be required for Nrf2 nuclear translocation [43]. Nrf2 is a transcription factor that is part of the StRE and EpRE binding complexes, which may also be involved in HO-1 gene regulation [31,44,45]. No change in total EpRE binding was observed after treatment with HNE (data not shown).…”

Section: Resultsmentioning

confidence: 92%

“…c-Jun can form part of the AP-1, StRE [31], and EpRE binding complexes [64] and further, StRE-and EpRE-mediated induction of HO-1 has been shown previously in rat cell lines [31,64,65]. Although no change in total EpRE binding was observed in response to HNE, the EpRE and/ or StRE enhancer elements could still be involved in the increase in HO-1 mRNA via transcription factor complex remodeling [39], specifically through activated c-Jun joining the complex and potentially displacing an inhibitor [66].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of AP-1 involves expression of AP-1-driven genes that include c-Jun. c-Jun may also form part of the stress response (StRE) and electrophile response elements (EpRE), also key regulators of redox-sensitive genes [30,31].HO-1 gene and protein expression is also modulated by MAPK activation. Seminal studies support a role for these kinases as mediators of HO-1 induction in a broad range of tissues and cell types.…”

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confidence: 99%

“…9). There was a rapid turnon/turn-off of this signal, with nuclear Nrf2 levels returning to baseline by 4 h postincubation.MafG has also been reported to be part of the StRE and EpRE binding complexes [31,39,46,47]. In some reports it has been identified as an inhibitor [46] and in other reports as a positive regulator of transcription [47].…”

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HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNEmediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. Keywords 4-Hydroxynonenal; Oxidative stress; HO-1; MAPK signaling; Free radicals Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme and widely accepted marker of oxidative stress. HO-1 catalyzes the first and rate-limiting step in the catabolism of heme, which generates equimolar amounts of biliverdin, ferrous iron, and carbon monoxide [1][2][3]. Although heme is the major substrate of HO-1, a variety of non-heme-containing agents are also strong inducers of HO-1. HO-1 has been shown to respond to a number of proinflammatory cytokines, including TNF-α, . HO-1 is also induced by a variety of agents NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that cause oxidative stress and/or in response to environmental stress [5][6][7][8]. For example, increased HO-1 expression has recently been found in the alveolar spaces in the resident macrophages of smokers [9]. Once induced, HO-1 provides protection against multiple types of tissue injury [10][11][12][13]; specific to the lung, overexpression of HO-1 in pulmonary epithelial cells has been shown to protect against oxygen toxicity [14]. In contrast, HO-1 deficiency in mice (HO-1 −/− ) increases susceptibility to inflammatory lung injury [15], as does HO-1 deficiency in humans [16]. Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s...

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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Neurodegeneration from Drugs and Aging‐Derived Free Radicals

Ramkissoon¹,

Shapiro²,

Loniewska³

et al. 2013

Molecular Basis of Oxidative Stress

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Effects of anthocyanin‐rich tea “Sunrouge” on dextran sodium sulfate‐induced colitis in mice

et al. 2012

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Sunrouge, an anthocyanin-rich tea, has similar levels of catechins as "Yabukita," the most popular green tea cultivar consumed in Japan. Green tea polyphenols (GTPs) have attracted interest due to their potent antioxidative activities combined with a lack of side effects in humans at normal consumption levels. However, we previously reported that high doses (0.5 and 1%) of dietary GTPs can result in deterioration of colitis and failed to prevent colon carcinogenesis in inflamed colons. In the present study, we determined the inhibitory effects of Sunrouge on colitis in dextran sodium sulfate (DSS)-treated and untreated control mice. Five-week-old female ICR mice were administered a single dose of Yabukita or Sunrouge (extracts in 1 mL distilled water) via a stomach tube for 3 weeks. After 1 week of treatment, the mice were divided into four groups (two Yabukita and two Sunrouge groups) and given drinking water with or without 3% DSS for 2 weeks, then they were euthanized. Those treated with DSS developed watery diarrhea and bloody stools, and showed body weight loss, spleen hypertrophy, and shortening of the colon, as well as deteriorations in survival rate, liver function, colon mucosal interleukin-1β level and expression of phase II detoxification enzyme mRNA. Sunrouge improved these DSS-induced symptoms, at least in part, whereas Yabukita showed either no effect or adverse effects in regard to some those parameters. It is suggested that the differences between Yabukita and Sunrouge on DSS-induced colitis might be due to the high levels of anthocyanins found in Sunrouge tea.

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Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2

Cited by 154 publications

References 51 publications

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Neurodegeneration from Drugs and Aging‐Derived Free Radicals

Effects of anthocyanin‐rich tea “Sunrouge” on dextran sodium sulfate‐induced colitis in mice

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