Angiotensin

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Angiotensinogen (serpin peptidase inhibitor, clade A, member 8)
250px Space-filling models of angiotensin I (left) and II (right). From PDB 1N9U and 1N9V.
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 • type 1 angiotensin receptor binding • type 2 angiotensin receptor binding Cellular component • extracellular region • extracellular space • soluble fraction Biological process • ovarian follicle rupture • blood vessel development • ureteric bud branching • kidney development • angiotensin mediated vasoconstriction during regulation of blood pressure • renal response to blood flow during renin-angiotensin regulation of blood pressure • renin-angiotensin regulation of aldosterone production • angiotensin mediated regulation of renal output • brain renin-angiotensin system • cell-matrix adhesion • cell surface receptor linked signal transduction • cell-cell signaling • female pregnancy • establishment of blood-nerve barrier • blood pressure regulation • negative regulation of cell proliferation • response to cold • extracellular matrix organization and biogenesis • peristalsis • positive regulation of body size • hormone metabolic process • drinking behavior • positive regulation of MAPKKK cascade • negative regulation of neuron apoptosis • positive regulation of fatty acid biosynthetic process • positive regulation of organ size • astrocyte activation • smooth muscle cell proliferation • smooth muscle cell differentiation Sources: Amigo / EGO
RNA expression pattern
250px
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: 228.9 - 228.92 Mb	Chr 8: 127.44 - 127.46 Mb
PubMed search	[1]	[2]

Angiotensin, a protein, causes blood vessels to constrict, and drives blood pressure up. 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 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 in the blood that causes vasoconstriction, increased blood pressure, and release of aldosterone from the adrenal cortex. It 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 that is 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

File:Renin-angiotensin-aldosterone system.png

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 both decreased intra-renal blood pressure at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If more Na+ is sensed, renin release is decreased.

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

Angiotensin I is converted to angiotensin II through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE, or kinase), which is found predominantly in the capillaries of the lung. ACE is actually found all over the body, but has its highest density in the lung due to the high density of capillary beds there. 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 angiotensin II 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 inhibitor drugs are major drugs against hypertension.

Other cleavage products of ACE, 7 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 angiotensin II itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT₁ receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases that are 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.

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 & IV have a number of effects throughout the body:

Cardiovascular effects

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 production 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 A1 adrenoreceptors.

Neural effects

Angiotensin II increases thirst sensation (dipsogen) through the subfornical organ (SFO) 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 effects

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 effects

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 as 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.

Renal effects of Angiotensin II

Target	Action	Mechanism
Renal artery & afferent arterioles	vasoconstriction	VDCCs → Ca2+ influx
efferent arteriole	vasoconstriction	(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
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
• Peptides

Further reading

• de Gasparo M, Catt KJ, Inagami T; et al. (2000). "International union of pharmacology. XXIII. The angiotensin II receptors". Parmacol Rev. 52 (3): 415–472. PMID 10977869. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 16597412. CS1 maint: Multiple names: authors list (link)
• Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]". Rev. Invest. Clin. 59 (1): 48–56. PMID 17569300. CS1 maint: Multiple names: authors list (link)

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External links

• The MEROPS online database for peptidases and their inhibitors: I04.953
• MeSH Angiotensins

ca:Angiotensina zh:血管紧张素