TY - JOUR
T1 - Transcriptional Regulation of Angiotensinogen Gene Expression
AU - Brasier, Allan R.
AU - Han, Youqi
AU - Sherman, Christopher T.
N1 - Funding Information:
This work was supported by grants from the CTR (4017, A.R.B.) and NHLBI (1R01 55630-01A1, A.R.B.). A.R.B. is an Established Investigator of the American Heart Association.
PY - 1997
Y1 - 1997
N2 - The renin-angiotensin system (RAS) is an extracellular hormonal system implicated in acute, homeostatic control of peripheral vascular resistance and electrolyte homeostasis. In this tightly regulated system, physiological regulators of blood pressure and fluid balance induce the production of the potent vasoactive angiotensin peptides by sequential proteolysis of the angiotensinogen (AGT) prohormone. AGT is the only known precursor of the angiotensin peptides, whose circulating concentrations influence the tonic activity of the RAS. AGT abundance is regulated at the transcriptional level through hormonal and cell-type specific regulators. In this review, we will discuss the identified mechanisms controlling AGT expression separately for the rodent and human genes. The most intensively investigated gene (rodent AGT) is regulated constitutively by multiple positive- and negative-acting cis factors that function in a cell-type dependent fashion. Inducible rodent AGT expression is mediated through a multihormone-inducible enhancer that integrates signals from steroid and cytokine hormones into AGT transcription. We review recent advances in understanding the mechanism of the nuclear factor-κB (NF-κB) family in mediating cytokine-induced AGT expression and our recent discoveries on the existence of differentially inducible pools of cytoplasmic NF-κB. Constitutive control of the human AGT gene will be discussed; there is surprisingly little information on the cis- and trans-acting regulators controlling inducible expression of human AGT. Finally, we will explore some of the recent developments in gene linkage studies where human AGT alleles have been associated with hypertensive phenotypes through a mechanism that may involve enhanced transcription. These studies have provided a molecular explanation for a subset of heritable hypertensive disorders in humans.
AB - The renin-angiotensin system (RAS) is an extracellular hormonal system implicated in acute, homeostatic control of peripheral vascular resistance and electrolyte homeostasis. In this tightly regulated system, physiological regulators of blood pressure and fluid balance induce the production of the potent vasoactive angiotensin peptides by sequential proteolysis of the angiotensinogen (AGT) prohormone. AGT is the only known precursor of the angiotensin peptides, whose circulating concentrations influence the tonic activity of the RAS. AGT abundance is regulated at the transcriptional level through hormonal and cell-type specific regulators. In this review, we will discuss the identified mechanisms controlling AGT expression separately for the rodent and human genes. The most intensively investigated gene (rodent AGT) is regulated constitutively by multiple positive- and negative-acting cis factors that function in a cell-type dependent fashion. Inducible rodent AGT expression is mediated through a multihormone-inducible enhancer that integrates signals from steroid and cytokine hormones into AGT transcription. We review recent advances in understanding the mechanism of the nuclear factor-κB (NF-κB) family in mediating cytokine-induced AGT expression and our recent discoveries on the existence of differentially inducible pools of cytoplasmic NF-κB. Constitutive control of the human AGT gene will be discussed; there is surprisingly little information on the cis- and trans-acting regulators controlling inducible expression of human AGT. Finally, we will explore some of the recent developments in gene linkage studies where human AGT alleles have been associated with hypertensive phenotypes through a mechanism that may involve enhanced transcription. These studies have provided a molecular explanation for a subset of heritable hypertensive disorders in humans.
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U2 - 10.1016/S0083-6729(08)60645-7
DO - 10.1016/S0083-6729(08)60645-7
M3 - Article
C2 - 10232051
AN - SCOPUS:0032601983
SN - 0083-6729
VL - 57
SP - 217
EP - 247
JO - Vitamins and Hormones
JF - Vitamins and Hormones
IS - C
ER -