Mechanisms for inducible control of angiotensinogen gene transcription

Allan R. Brasier, Junyi Li

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

The intravascular renin-angiotensin system is an endocrine system designed to maintain cardiovascular homeostasis in response to hypotension. Under normal conditions, angiotensinogen concentrations circulating in the plasma are rate limiting for the maximum velocity of angiotensin I formation. In the liver, the major site of circulating angiotensinogen synthesis, angiotensinogen expression is under exquisite hormonal control. We review the mechanisms by which hormones effect transcriptional control of angiotensinogen expression. Adrenal-derived glucocorticoids produce the translocation of the glucocorticoid receptor into the nucleus. It in turn binds to two glucocorticoid response elements and stimulates angiotensinogen gene transcription. Inflammation activates angiotensinogen transcription as a result of the macrophage-derived cytokines interleukin-l and tumor necrosis factor-α. These cytokines change the abundance of two transcription factor families that bind a single regulatory site in the angiotensinogen promoter, the acute-phase response element. These proteins include the nuclear factor-κB complex and the CCAAT/enhancer binding protein family. Activation of the renin-angiotensin system, through production of angiotensin II, results in feedback stimulation of angiotensinogen synthesis (the 'positive feedback loop'). We have discovered that the nuclear factor-κB transcription factor is regulated by angiotensin II, a finding that provides a mechanism for the transcriptional component of angiotensinogen gene synthesis in the positive feedback loop. These studies underscore the concept that induction of the angiotensinogen gene by diverse physiological stimuli is mediated through changes in the nuclear abundance of sequence-specific transcription factors. The intracellular convergence of cytokine- and angiotensin II-induced signaling pathways on the nuclear factor-κB transcription factor provides a point for 'cross talk' between angiotensin- and cytokine-activated second messenger pathways.

Original languageEnglish (US)
Pages (from-to)465-475
Number of pages11
JournalHypertension
Volume27
Issue number3 II
DOIs
StatePublished - Mar 1996
Externally publishedYes

Keywords

  • angiotensinogen
  • nuclear factor-IL6
  • nuclear factor-κB

ASJC Scopus subject areas

  • Internal Medicine

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