Angiotensin

Angiotensinogen (serpin peptidase inhibitor, clade A, member 8)
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1N9U, 1N9V, 2JP8, 2WXW, 2X0B, 4AA1, 4APH, 4FYS
Identifiers
Symbols	AGT; ANHU; SERPINA8
External IDs	OMIM: 106150 MGI: 87963 HomoloGene: 14 GeneCards: AGT Gene
Gene Ontology Molecular function • serine-type endopeptidase inhibitor activity • hormone activity • growth factor activity • acetyltransferase activator activity • type 1 angiotensin receptor binding • type 2 angiotensin receptor binding Cellular component • extracellular region • extracellular space • cytoplasmic part Biological process • ovarian follicle rupture • regulation of cell growth • blood vessel development • branching involved in ureteric bud morphogenesis • positive regulation of cytokine production • kidney development • blood vessel remodeling • angiotensin mediated vasoconstriction involved in regulation of systemic arterial blood pressure • renal response to blood flow involved in circulatory renin-angiotensin regulation of systemic arterial blood pressure • angiotensin maturation • regulation of blood volume by renin-angiotensin • renin-angiotensin regulation of aldosterone production • regulation of renal output by angiotensin • regulation of blood vessel size by renin-angiotensin • angiotensin-mediated drinking behavior • positive regulation of extracellular matrix constituent secretion • cellular sodium ion homeostasis • induction of apoptosis • cell-matrix adhesion • G-protein coupled receptor signaling pathway • G-protein coupled receptor signaling pathway coupled to cGMP nucleotide second messenger • phospholipase C-activating G-protein coupled receptor signaling pathway • activation of phospholipase C activity • activation of NF-kappaB-inducing kinase activity • nitric oxide mediated signal transduction • cell-cell signaling • aging • excretion • establishment of blood-nerve barrier • negative regulation of cell proliferation • response to cold • response to salt stress • positive regulation of activation of JAK2 kinase activity • positive regulation of endothelial cell migration • positive regulation of cardiac muscle hypertrophy • positive regulation of macrophage derived foam cell differentiation • positive regulation of cholesterol esterification • negative regulation of endopeptidase activity • regulation of norepinephrine secretion • positive regulation of phosphatidylinositol 3-kinase cascade • artery smooth muscle contraction • response to muscle activity involved in regulation of muscle adaptation • regulation of vasoconstriction • regulation of proteolysis • extracellular matrix organization • negative regulation of cell growth • peristalsis • positive regulation of cellular protein metabolic process • positive regulation of superoxide anion generation • positive regulation of NAD(P)H oxidase activity • negative regulation of tissue remodeling • low-density lipoprotein particle remodeling • catenin import into nucleus • regulation of renal sodium excretion • positive regulation of renal sodium excretion • positive regulation of multicellular organism growth • regulation of cell proliferation • vasodilation • positive regulation of apoptotic process • positive regulation of MAPK cascade • negative regulation of neuron apoptotic process • cellular lipid metabolic process • cellular protein metabolic process • small molecule metabolic process • positive regulation of fatty acid biosynthetic process • positive regulation of epidermal growth factor receptor signaling pathway • positive regulation of transcription, DNA-dependent • positive regulation of organ growth • astrocyte activation • fibroblast proliferation • positive regulation of fibroblast proliferation • regulation of long-term neuronal synaptic plasticity • smooth muscle cell proliferation • cytokine secretion • positive regulation of inflammatory response • positive regulation of peptidyl-tyrosine phosphorylation • positive regulation of NF-kappaB transcription factor activity • smooth muscle cell differentiation • negative regulation of neurotrophin TRK receptor signaling pathway • stress-activated MAPK cascade • regulation of calcium ion transport • cell growth involved in cardiac muscle cell development • positive regulation of protein tyrosine kinase activity • ERK1 and ERK2 cascade • cellular response to mechanical stimulus • positive regulation of branching involved in ureteric bud morphogenesis • positive regulation of reactive oxygen species metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	183	11606
Ensembl	ENSG00000135744	ENSMUSG00000031980
UniProt	P01019	Q3UTR7
RefSeq (mRNA)	NM_000029	NM_007428
RefSeq (protein)	NP_000020	NP_031454
Location (UCSC)	Chr 1: 230.84 – 230.85 Mb	Chr 8: 124.56 – 124.57 Mb
PubMed search	[1]	[2]

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up.

Angiotensin is an oligopeptide and is a hormone and a powerful dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. It plays an important role in the renin-angiotensin system. Angiotensin was independently isolated in Indianapolis and Argentina in the late 1930s (as 'angiotonin' and 'hypertensin', respectively) and subsequently characterised and synthesized by groups at the Cleveland Clinic and Ciba laboratories in Basel, Switzerland.

Precursor, and types of angiotensin

Angiotensinogen

Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels.

Angiotensinogen is also known as renin substrate. Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...

Angiotensin I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...

Renin-angiotensin-aldosterone system

Angiotensin I (CAS# 11128-99-7) is formed by the action of renin on angiotensinogen. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure ) at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If less Na+ is sensed by the macula densa, renin release by juxtaglomerular cells is increased.

Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the ten-amino acid peptide (des-Asp) angiotensin I (CAS# 9041-90-1).

Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin 2.

Angiotensin II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | His-Leu

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial and kidney epithelial cells). ACE found in other tissues of the body has no physiological role (ACE has a high density in the lung, but activation here promotes no vasoconstriction, angiotensin II is below physiological levels of action).^{[citation needed]} Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of AII production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates contraction by an IP3-dependent mechanism). ACE inhibitors are major anti-hypertensive drugs.

Other cleavage products of ACE, seven or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT₁ receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes.

Angiotensin III

Asp | Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases MAP

Angiotensin IV

Arg | Val-Tyr-Ile-His-Pro-Phe

Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity.

Effects

See also Renin-angiotensin_system#Effects

Angiotensins II, III and IV have a number of effects throughout the body:

Adipic

Angiotensin "modulate fat mass expansion through upregulation of adipose tissue lipogenesis ... and downregulation of lipolysis "

Cardiovascular

They are potent direct vasoconstrictors, constricting arteries and veins and increasing blood pressure.

Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.

When cardiac cell growth is stimulated, a local (autocrine-paracrine) renin-angiotensin system is activated in the cardiac myocyte, which stimulates cardiac cell growth through protein kinase C. The same system can be activated in smooth muscle cells in conditions of hypertension, atherosclerosis, or endothelial damage. Angiotensin II is the most important Gq stimulator of the heart during hypertrophy, compared to endothelin-1 and α1 adrenoreceptors.^{[citation needed]}

Neural

Angiotensin II increases thirst sensation (dipsogen) through the subfornical organ of the brain, decreases the response of the baroreceptor reflex, and increases the desire for salt. It increases secretion of ADH in the posterior pituitary and secretion of ACTH in the anterior pituitary. It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers.

Adrenal

Angiotensin II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium. Elevated plasma angiotensin II levels are responsible for the elevated aldosterone levels present during the luteal phase of the menstrual cycle.

Renal

Angiotensin II has a direct effect on the proximal tubules to increase Na⁺ reabsorption. It has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting. Increases in systemic blood pressure will maintain renal perfusion pressure; however, constriction of the afferent and efferent glomerular arterioles will tend to restrict renal blood flow. The effect on the efferent arteriolar resistance is, however, markedly greater, in part due to its smaller basal diameter; this tends to increase glomerular capillary hydrostatic pressure and maintain glomerular filtration rate. A number of other mechanisms can affect renal blood flow and GFR. High concentrations of Angiotensin II can constrict the glomerular mesangium, reducing the area for glomerular filtration. Angiotensin II is a sensitizer to tubuloglomerular feedback, preventing an excessive rise in GFR. Angiotensin II causes the local release of prostaglandins, which, in turn, antagonize renal vasoconstriction. The net effect of these competing mechanisms on glomerular filtration will vary with the physiological and pharmacological environment.

Direct Renal effects of angiotensin II (not including aldosterone release)

Target	Action	Mechanism
renal artery & afferent arterioles	vasoconstriction (weaker)	VDCCs → Ca2+ influx
efferent arteriole	vasoconstriction (stronger)	(probably) activate Angiotensin receptor 1 → Activation of Gq → ↑PLC activity → ↑IP3 and DAG → activation of IP3 receptor in SR → ↑intracellular Ca2+
mesangial cells	contraction → ↓filtration area	activation of Gq → ↑PLC activity → ↑IP3 and DAG → activation of IP3 receptor in SR → ↑intracellular Ca2+ VDCCs → Ca2+ influx
proximal tubule	increased Na+ reabsorption	adjustment of Starling forces in peritubular capillaries to favour increased reabsorption efferent arteriole contraction → decreased hydrostatic pressure in peritubular capillaries efferent arteriole contraction → increased filtration fraction → increased colloid osmotic pressure in peritubular capillaries increased sodium–hydrogen antiporter activity
tubuloglomerular feedback	increased sensitivity	increase in afferent arteriole responsiveness to signals from macula densa
medullary blood flow	reduction

See also

• ACE inhibitor
• Angiotensin receptor
• Angiotensin II receptor antagonist
• Captopril
• Renin inhibitor

Further reading

• de Gasparo M, Catt KJ, Inagami T, "" et al. (2000). "International union of pharmacology. XXIII. The angiotensin II receptors". Pharmacol Rev. 52 (3): 415–472. PMID 10977869. 
• Brenner & Rector's The Kidney, 7th ed., Saunders, 2004.
• Mosby's Medical Dictionary, 3rd Ed., CV Mosby Company, 1990.
• Review of Medical Physiology, 20th Ed., William F. Ganong, McGraw-Hill, 2001.
• Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed., Burton David Rose & Theodore W. Post McGraw-Hill, 2001
• Lees KR, MacFadyen RJ, Doig JK, Reid JL (1993). "Role of angiotensin in the extravascular system". Journal of Human Hypertension. 7 Suppl 2: S7–12. PMID 8230088. 
• Weir MR, Dzau VJ (2000). "The renin-angiotensin-aldosterone system: a specific target for hypertension management". Am. J. Hypertens. 12 (12 Pt 3): 205S–213S. doi:10.1016/S0895-7061(99)00103-X. PMID 10619573. 
• Berry C, Touyz R, Dominiczak AF et al. (2002). "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide". Am. J. Physiol. Heart Circ. Physiol. 281 (6): H2337–65. PMID 11709400. 
• Sernia C (2002). "A critical appraisal of the intrinsic pancreatic angiotensin-generating system". JOP 2 (1): 50–5. PMID 11862023. 
• Varagic J, Frohlich ED (2003). "Local cardiac renin-angiotensin system: hypertension and cardiac failure". J. Mol. Cell. Cardiol. 34 (11): 1435–42. doi:10.1006/jmcc.2002.2075. PMID 12431442. 
• Wolf G (2006). "Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis". Antioxid. Redox Signal. 7 (9–10): 1337–45. doi:10.1089/ars.2005.7.1337. PMID 16115039. 
• Cazaubon S, Deshayes F, Couraud PO, Nahmias C (2006). "[Endothelin-1, angiotensin II and cancer]". Med Sci (Paris) 22 (4): 416–22. doi:10.1051/medsci/2006224416. PMID 16597412. 
• Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]". Rev. Invest. Clin. 59 (1): 48–56. PMID 17569300. 

External links

• The MEROPS online database for peptidases and their inhibitors: I04.953
• Angiotensins at the US National Library of Medicine Medical Subject Headings (MeSH)