Posttranscriptional regulation of human iNOS by the NO/cGMP pathway

Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1beta plus tumor necrosis factor (...

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2001-03, Vol.280 (3), p.F466-F473
Main Authors: Pérez-Sala, D, Cernuda-Morollón, E, Díaz-Cazorla, M, Rodríguez-Pascual, F, Lamas, S
Format: Article
Language:English
Subjects:
Cells, Cultured
Cyclic GMP - analogs & derivatives
Cyclic GMP - pharmacology
Cyclic GMP - physiology
Enzyme Induction
Enzyme Inhibitors - pharmacology
Glomerular Mesangium - metabolism
Humans
Interleukin-1 - pharmacology
Nitric Oxide - physiology
Nitric Oxide Donors - pharmacology
Nitric Oxide Synthase - antagonists & inhibitors
Nitric Oxide Synthase - genetics
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Oxadiazoles - pharmacology
Quinoxalines - pharmacology
RNA Stability - drug effects
RNA, Messenger - metabolism
Transcription, Genetic - physiology
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1beta plus tumor necrosis factor (TNF)-alpha reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1beta/TNF-alpha-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.2001.280.3.F466