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Dual Effect of Nitric Oxide Donors on Cyclooxygenase-2 Expression in Human Mesangial Cells

1999; American Society of Nephrology; Volume: 10; Issue: 5 Linguagem: Inglês

10.1681/asn.v105943

1533-3450

Manuela Dı́az-Cazorla, Dolores Pérez‐Sala, Santiago Lamas,

NF-κB Signaling Pathways

Abstract. Nitric oxide (NO) is emerging as a key regulator of gene expression, capable of playing either positive or negative roles. The results of this study indicate that NO exerts a dual effect on cyclooxygenase-2 (COX-2) expression in human mesangial cells (HMC). Treatment of HMC with NO synthase inhibitors attenuated interleukin-1β (IL-1β)/tumor necrosis factor-α (TNF-α)-elicited COX-2 protein and mRNA expression, suggesting a positive role of endogenous NO on COX-2 induction. However, NO donors (sodium nitroprusside [SNP] and S-nitroso- N -acetylpenicillamine [SNAP]) amplified cytokine-elicited COX-2 expression at early time points of treatment (up to 8 h for mRNA and up to 24 h for protein expression), but were inhibitory at later times. Oligonucleotide decoy experiments confirmed the importance of nuclear factor κB (NF-κB) activation for COX-2 induction by IL-1β/TNF-α. Treatment with N G -nitro-L-arginine methyl ester (L-NAME) did not affect initial activation of NF-κB by IL-1β/TNF-α, but unveiled an inhibitory effect of NO generation on NF-κB activity after 4 h. In HMC supplemented with SNP, cytokine-induced NF-κB activation was potentiated at early times of induction (5 to 15 min), but inhibited at later times (1 to 4 h), suggesting a dual effect of NO donors on NF-κB activation. Interestingly, IκBα protein levels followed a reciprocal pattern of expression: IκBα levels were lower at early times of induction in NO donor-supplemented cells; however, after 1 h of treatment, IκBα levels became higher than in cells treated only with cytokines. In the presence of SNP, cytokine-elicited IκBα mRNA induction was initially delayed, but was amplified at later times. These changes in IκBα expression could contribute to the dual effects of NO donors on NF-κB activation and COX-2 expression in HMC.