Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element
Top Cited Papers
- 1 May 2003
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 371 (3), 887-895
- https://doi.org/10.1042/bj20021619
Abstract
The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.Keywords
This publication has 41 references indexed in Scilit:
- The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic MouseJournal of Neuroscience, 2001
- Dietary Curcuminoids Prevent High-Fat Diet–Induced Lipid Accumulation in Rat Liver and Epididymal Adipose TissueJournal of Nutrition, 2001
- Phytochemicals from Cruciferous Plants Protect against Cancer by Modulating Carcinogen MetabolismJournal of Nutrition, 2001
- Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cellsAmerican Journal of Physiology-Renal Physiology, 2001
- Nrf2-deficient female mice develop lupus-like autoimmune nephritis11See Editorial by Byrd and Thomas, p. 1606.Kidney International, 2001
- Induction of Cellular Antioxidative Stress Genes through Heterodimeric Transcription Factor Nrf2/Small Maf by Antirheumatic Gold(I) CompoundsPublished by Elsevier BV ,2001
- Curcumin and Especially Tetrahydrocurcumin Ameliorate Oxidative Stress-Induced Renal Injury in MiceJournal of Nutrition, 2001
- An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophenProceedings of the National Academy of Sciences of the United States of America, 2001
- Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groupsProceedings of the National Academy of Sciences of the United States of America, 2001
- Regulation of genes encoding NAD(P)H:quinone oxidoreductasesFree Radical Biology & Medicine, 2000