MECHANISMS FOR INDUCIBLE CONTROL OF ANGIOTENSINOGEN GENE-TRANSCRIPTION

The intravascular renin-angiotensin system is an endocrine system desi gned 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 angiotensi n I formation. In the liver, the major site of circulating angiotensin ogen synthesis, angiotensinogen expression is under exquisite hormonal control. We review the mechanisms by which hormones effect transcript ional control of angiotensinogen expression. Adrenal-derived glucocort icoids produce the translocation of the glucocorticoid receptor into t he nucleus. It in turn binds to two glucocorticoid response elements a nd stimulates angiotensinogen gene transcription. Inflammation activat es angiotensinogen transcription as a result of the macrophage-derived cytokines interleukin-1 and tumor necrosis factor-alpha. These cytoki nes change the abundance of two transcription factor families that bin d a single regulatory site in the angiotensinogen promoter, the acute- phase response element. These proteins include the nuclear factor-kapp a B 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 ''p ositive feedback loop''). We have discovered that the nuclear factor-k appa B transcription factor is regulated by angiotensin II, a finding that provides a mechanism for the transcriptional component of angiote nsinogen gene synthesis in the positive feedback loop. These studies u nderscore the concept that induction of the angiotensinogen gene by di verse physiological stimuli is mediated through changes in the nuclear abundance of sequence-specific transcription factors. The intracellul ar convergence of cytokine- and angiotensin II-induced signaling pathw ays on the nuclear factor-kappa B transcription factor provides a poin t for ''cross talk'' between angiotensin- and cytokine-activated secon d messenger pathways.