NF-κB and CREB Are Required for Angiotensin II Type 1 Receptor Upregulation in Neurons

Nuclear factor kappa B (NF-κB) and the Ets like gene-1 (Elk-1) are two transcription factors that have been previously established to contribute to the Angiotensin II mediated upregulation of Angiotensin II type 1 receptor (AT1R) in neurons. The cAMP response element binding protein (CREB) is anothe...

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Vydáno v:	PloS one Ročník 8; číslo 11; s. e78695
Hlavní autoři:	Haack, Karla K. V., Mitra, Amit K., Zucker, Irving H.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 11.11.2013 Public Library of Science (PLoS)
Témata:	Angiotensin Angiotensin II Angiotensin II - pharmacology Anti-Inflammatory Agents, Non-Steroidal - pharmacology Ca2+/calmodulin-dependent protein kinase Calcium-binding protein Calmodulin Cell Line Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - genetics Cyclic AMP Response Element-Binding Protein - metabolism Deoxyribonucleic acid DNA Electrophoretic mobility Elk ETS protein ets-Domain Protein Elk-1 - genetics ets-Domain Protein Elk-1 - metabolism Gene expression Heart failure Humans Hypertension Imidazoles - pharmacology Inhibition Kinases MAP kinase Metastasis Molecular modelling Neurons NF-kappa B - genetics NF-kappa B - metabolism NF-κB protein p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Physiology Proteins Pyridines - pharmacology Receptor, Angiotensin, Type 1 - biosynthesis Receptor, Angiotensin, Type 1 - genetics Renin Rodents Signaling siRNA Smooth muscle Transcription activation Transcription factors Up-regulation Up-Regulation - drug effects Up-Regulation - physiology Vasoconstrictor Agents - pharmacology United States > US Nebraska
ISSN:	1932-6203, 1932-6203
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Popis
Shrnutí:	Nuclear factor kappa B (NF-κB) and the Ets like gene-1 (Elk-1) are two transcription factors that have been previously established to contribute to the Angiotensin II mediated upregulation of Angiotensin II type 1 receptor (AT1R) in neurons. The cAMP response element binding protein (CREB) is another transcription factor that has also been implicated in AT1R gene transcription. The goal of the current study was to determine if NF-κB and CREB association was required for AT1R upregulation. We hypothesized that the transcription of the AT1R gene occurs via an orchestration of transcription factor interactions including NF-κB, CREB, and Elk-1. The synergistic role of CREB and NFκB in promoting AT1R gene expression was determined using siRNA-mediated silencing of CREB. Electrophorectic Mobility Shift Assay studies employing CREB and NF-κB demonstrated increased protein - DNA binding as a result of Ang II stimulation which was blunted by siRNA silencing of CREB. Upstream inhibition of p38 mitogen activated protein kinase (p38 MAPK) with SB203580 or inhibition of the calmodulin kinase (CAMK) pathway using KN-62 blunted changes in CREB and NF-κB expression. These findings suggest that Ang II may activate multiple signaling pathways involving p38 MAPK leading to the activation of NF-κB and CREB, which feed back to upregulate the AT1R gene. This study provides insight into the molecular mechanisms involving multiple transcription factor activation in a coordinated fashion which may be partially responsible for sympathoexcitation in clinical conditions associated with increased activation of the renin angiotensin system.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: IHZ KVH AKM. Performed the experiments: KVH AKM. Analyzed the data: KVH AKM. Wrote the paper: IHZ KVH AKM.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0078695