Dual role of heme oxygenase in epithelial cell injury: Contrasting effects of short-term and long-term exposure to oxidant stress

Silva, Jean-Louis Da; Morishita, Takahiro; Escalante, Bruno; Staudinger, Robert; Drummond, George I.; Goligorsky, Michael S.; Lutton, John D.; Abraham, Nader G.

doi:10.1016/s0022-2143(96)90030-x

Cited by 72 publications

(57 citation statements)

References 27 publications

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“…Data from several laboratories demonstrated that directly after inducing HO-1, cells are sensitized to oxidative stress, whereas after prolonged time, ferritin is upregulated, and these cells are desensitized and significantly protected against a wide range of stresses (Balla et al, 1993;da Silva et al, 1996;Ryter and Tyrrell, 2000). It is evident that each of the heme breakdown products, when present in high quantities can mediate cell injury instead of cytoprotection (Fig.…”

Section: Some Considerations Concerning Modulation Of the Heme-hemmentioning

confidence: 99%

Different Faces of the Heme-Heme Oxygenase System in Inflammation

et al. 2003

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Section: Some Considerations Concerning Modulation Of the Heme-hemmentioning

confidence: 99%

Different Faces of the Heme-Heme Oxygenase System in Inflammation

et al. 2003

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“…HO-1 is upregulated in nephrotoxicity, and its enhanced expression is regarded as a marker of oxidative stress (16 -22). It is increased in response to a number of injury-causing chemicals, including H 2 O 2 , and may provide protection against cell injury (23,24). The purpose of the next series of experiments was to examine the expression of SSAT and HO-1 with respect to each other in two groups of rats with mild and severe renal ischemic injury.…”

Section: Upregulation Of Ssat and Ho-1 In Vivo Is An Early Event And mentioning

confidence: 99%

Overexpression of SSAT in Kidney Cells Recapitulates Various Phenotypic Aspects of Kidney Ischemia-reperfusion Injury

Wang

Zahedi²,

Barone

et al. 2004

Journal of the American Society of Nephrology

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Abstract. To ascertain the role of spermidine/spermine N-1-acetyl-transferase (SSAT; the rate-limiting enzyme in polyamine catabolism) in cell injury, cultured kidney (HEK 293) cells conditionally overexpressing SSAT were generated. The SSAT expression was induced and its enzymatic activity increased 24 h after addition of tetracycline and remained elevated over the length of the experiments. Induction of SSAT upregulated the expression of polyamine oxidase and resulted in the reduction of cellular concentration of spermidine and spermine, increased concentration of putrescine, and inhibited cell growth. SSAT overexpression increased the expression of heme oxygenase-1 (HO-1) by 350% 24 h after addition of tetracycline, indicating the induction of oxidative stress. The presence of catalase significantly prevented the upregulation of HO-1 in SSAT overexpressing cells, indicating that generation of H 2 O 2 is partially responsible for the induction of oxidative stress. Overexpression of SSAT caused rounding and loss of cell anchorage and significantly altered the morphology of actin-containing filopodia, suggesting an adhesion defect. SSAT upregulation may mediate majority of the oxidative stress in kidney ischemia-reperfusion injury (IRI) as manifested by decreased cell growth, generation of toxic metabolites (H 2 O 2 and putrescine), upregulation of HO-1, disruption of cell anchorage, and defect in cell adhesion. These data point to the inhibition of polyamine catabolism as a therapeutic approach for the prevention of tissue injury in kidney IRI.Ischemia-reperfusion injury (IRI) is the major cause of morbidity and mortality in diseases such as stroke, myocardial infarction, and acute renal tubular necrosis. Ischemic conditions result in ATP depletion and accumulation of toxic metabolites. Reperfusion results in the production of reactive oxygen intermediates (1,2). The resulting alteration in cellular metabolism and generation of toxic molecules contribute to tissue damage in IRI (1,2), which is characterized by the presence of necrotic and apoptotic areas in the affected organs (1,3). Despite important developments in our understanding of the pathophysiology of IRI in kidney, heart, and other organs, there is no specific therapy for patients except for supportive care.Polyamines (spermidine, spermine, and putrescine) are aliphatic cations derived from ornithine (4,5). They play a fundamental role in the stabilization of DNA structure; they modulate gene expression and regulate protein synthesis, signal transduction, and cell growth and differentiation (4,6 -8). Spermidine/spermine N-1-acetyl-transferase (SSAT; the rate-limiting enzyme in polyamine catabolism) acetylates both spermidine and spermine. As a result, the cellular contents of spermidine and spermine are decreased and the concentrations of N-acetyl spermidine and N-acetyl spermine are increased (9). The subsequent activity of polyamine oxidase (PAO) on acetylated polyamines results in the production of spermidine or putrescine (depending on the startin...

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“…Iron by itself is a potent oxidative stress agent, whereas the iron released by HO-1 activity further enhances ferritin synthesis and thereby its sequestering (23). In this regard, overexpres sion of HO-1 in endothelial cells has been shown to protect from heme-and hemoglobin-mediated toxicity (19), and is associated with increased tolerance of the cell to ischemia and trauma in a variety of tissues (24,25).…”

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confidence: 99%