Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells.
Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 occurs as an adaptive and protective response to several inflammatory stimuli. The transcription factor activator protein-1 (AP-1) has been implicated in the activation of the HO-1 gene. To elucidate the molecular mechanism of HO-1 induction, we examined the effects of diferuloylmethane (curcumin), an inhibitor of the transcription factor AP-1. Surprisingly, curcumin by itself was a very potent inducer of HO-1. Curcumin has anti-inflammatory, antioxidant, and renoprotective effects. To evaluate the mechanism of curcumin-mediated induction of HO-1, confluent human renal proximal tubule cells were exposed to curcumin (1-8 microM). We observed a time- and dose-dependent induction of HO-1 mRNA that was associated with increased HO-1 protein. Coincubation of curcumin with actinomycin D completely blocked the upregulation of HO-1 mRNA. Blockade of nuclear factor-kappaB (NF-kappaB) with an IkappaBalpha phosphorylation inhibitor attenuated curcumin-mediated induction of HO-1 mRNA and protein. These data demonstrate that curcumin induces HO-1 mRNA and protein in renal proximal tubule cells. HO-1 induction by curcumin is mediated, at least in part, via transcriptional mechanisms and involves the NF-kappaB pathway.
Hill-Kapturczak
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N
Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida, Gainesville, Florida 32610, USA.
Thamilselvan
V
V
Liu
F
F
Nick
H S
HS
Agarwal
A
A
D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005293:Ferritins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D006207:Half-Life; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006801:Humans; D015151:Immunoblotting; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003609:Dactinomycin; D005293:Ferritins; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011505:Protein-Tyrosine Kinases; D003474:Curcumin