Regulation of renin gene expression by oxidative stress.
Increased arterial pressure, angiotensin II, and cytokines each result in feedback inhibition of renin gene expression. Because angiotensin II and cytokines can stimulate reactive oxygen species production, we tested the hypothesis that oxidative stress may be a mediator of this inhibition. Treatment of renin-expressing As4.1 cells with the potent cytokine tumor necrosis factor-alpha caused an increase in the steady-state levels of cellular reactive oxygen species, which was reversed by the antioxidant N-acetylcysteine. Exogenous H(2)O(2) caused a dose- and time-dependent decrease in the level of endogenous renin mRNA and decreased the transcriptional activity of a 4.1-kb renin promoter fused to luciferase, which was maximal when the renin enhancer was present. The effect of H(2)O(2) appeared to be specific to renin, because there was no change in the expression of beta-actin or cyclophilin mRNA or transcriptional activity of the SV40 promoter. The tumor necrosis factor-alpha-induced decrease in renin mRNA was partially reversed by either N-acetylcysteine or panepoxydone, a nuclear factor kappaB (NFkappaB) inhibitor. Interestingly, H(2)O(2) did not induce NFkappaB in As4.1 cells, and panepoxydone had no effect on the downregulation of renin mRNA by H(2)O(2). The transcriptional activity of a cAMP response element-luciferase construct was decreased by both tumor necrosis factor-alpha and H(2)O(2). These data suggest that cellular reactive oxygen species can negatively regulate renin gene expression via an NFkappaB-independent mechanism involving the renin enhancer and inhibiting cAMP response element-mediated transcription. Our data further suggest that tumor necrosis factor-alpha decreases renin expression through both NFkappaB-dependent and NFkappaB-independent mechanisms, the latter involving the production of reactive oxygen species.
Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
Hana
H
Itani
Xuebo
X
Liu
Ehab H
EH
Sarsour
Prabhat C
PC
Goswami
Ella
E
Born
Henry L
HL
Keen
Curt D
CD
Sigmund
D000111:Acetylcysteine / Q000494:pharmacology; D000704:Analysis of Variance; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D008156:Luciferases / Q000032:analysis; D046228:Microarray Analysis; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D011336:Probability; D012313:RNA / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D008156:Luciferases; D012083:Renin; D000111:Acetylcysteine