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Angiotensin

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(Redirected fromAngiotensinogen)
angiotensins
Identifiers
Aliasesangiotensin
External IDsGeneCards:[1];OMA:- orthologs
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

n
a

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RefSeq (mRNA)

n/a

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMedsearchn/an/a
Wikidata
View/Edit Human

Angiotensinis apeptide hormonethat causesvasoconstrictionand an increase inblood pressure.It is part of therenin–angiotensin system,which regulates blood pressure. Angiotensin also stimulates the release ofaldosteronefrom theadrenal cortexto promote sodium retention by the kidneys.

Anoligopeptide,angiotensin is ahormoneand adipsogen.It is derived from the precursor molecule angiotensinogen, a serum globulin produced in theliver.Angiotensin was isolated in the late 1930s (first named 'angiotonin' or 'hypertensin') and subsequently characterized and synthesized by groups at theCleveland ClinicandCibalaboratories.[1]

Precursor and types

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See also:Angiotensin (1-7)

Angiotensinogen

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Crystal structure of reactive center loop cleaved angiotensinogen via x-ray diffraction
AGT
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesAGT,ANHU, SERPINA8, hFLT1, angiotensinogen
External IDsMGI:87963;HomoloGene:14;GeneCards:AGT;OMA:AGT - orthologs
Orthologs
SpeciesHumanMouse
Entrez

183

11606

Ensembl

ENSG00000135744

ENSMUSG00000031980

UniProt

P01019

P11859
Q3UTR7

RefSeq (mRNA)

NM_000029
NM_001382817
NM_001384479

NM_007428

RefSeq (protein)

NP_000020
NP_001369746

NP_031454

Location (UCSC)Chr 1: 230.69 – 230.75 MbChr 8: 125.28 – 125.3 Mb
PubMedsearch[4][5]
Wikidata
View/Edit HumanView/Edit Mouse

Angiotensinogen is anα-2-globulinsynthesized in the liver[6]and is a precursor for angiotensin, but has also been indicated as having many other roles not related to angiotensin peptides.[7]It is a member of theserpinfamily of proteins, leading to another name: Serpin A8,[8]although it is not known to inhibit other enzymes like most serpins. In addition, a generalized crystal structure can be estimated by examining other proteins of the serpin family, but angiotensinogen has an elongatedN-terminuscompared to other serpin family proteins.[9]Obtaining actual crystals for X-ray diffractometric analysis is difficult in part due to the variability of glycosylation that angiotensinogen exhibits. The non-glycosylated and fully glycosylated states of angiotensinogen also vary in molecular weight, the former weighing 53 kDa and the latter weighing 75 kDa, with a plethora of partially glycosylated states weighing in between these two values.[7]

Angiotensinogen is also known asreninsubstrate. It is cleaved at the N-terminus by renin to result in angiotensin I, which will later be modified to become angiotensin II.[7][9]This peptide is 485 amino acids long, and 10 N-terminus amino acids are cleaved when renin acts on it.[7]The first 12 amino acids are the most important for activity.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...[clarification needed]

Plasma angiotensinogen levels are increased by plasmacorticosteroid,estrogen,thyroidhormone,and angiotensin II levels. In mice with a full body deficit of angiotensinogen, the effects observed were low newborn survival rate, stunted body weight gain, stunted growth, and abnormal renal development.[7]

Angiotensin I

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Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...[clarification needed]
Renin–angiotensin–aldosterone system

Angiotensin I (CAS# 11128-99-7), officially calledproangiotensin,is formed by the action ofreninonangiotensinogen.Renin cleaves thepeptide bondbetween theleucine(Leu) andvaline(Val) residues on angiotensinogen, creating thedecapeptide(ten amino acid) (des-Asp) angiotensin I. Renin is produced in thekidneysin response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure[10]) at thejuxtaglomerular cells,dehydration or decreased delivery of Na+ and Cl- to themacula densa.[11]If a reduced NaCl concentration[12]in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased. This sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations ofthick ascending limbwithglomerulusattached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition ofchloridesalts.[13]This, and similar findings obtained in vivo,[14]has led some to believe that perhaps "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminalNa,K,2Cl co-transporterwhose physiological activity is determined by a change in luminal Cl concentration. "[15]

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

Angiotensin II

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See also:Angiotensin II (medication)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe[clarification needed]

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzymeangiotensin-converting enzyme(ACE), primarily through ACE within the lung (but also present inendothelial cells,kidney epithelial cells, and the brain). Angiotensin II acts on thecentral nervous systemto increasevasopressinproduction, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increasesaldosteronesecretion; it therefore acts as anendocrine,autocrine/paracrine,andintracrinehormone.

ACE is a target ofACE inhibitordrugs, 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 an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at theNa+/H+exchangerin theproximal tubulesof the kidney to stimulate Na+reabsorption and H+excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH.[16]Hence,ACE inhibitorsare major anti-hypertensive drugs.

Other cleavage products of ACE, seven or nine amino acids long, are also known; they have differential affinity forangiotensin receptors,although their exact role is still unclear. The action of AII itself is targeted byangiotensin II receptor antagonists,which directly blockangiotensin II AT1receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. Angiotensin II has a half-life in circulation of around 30 seconds,[17]whereas, in tissue, it may be as long as 15–30 minutes.

Angiotensin II results in increasedinotropy,chronotropy,catecholamine(norepinephrine) release, catecholamine sensitivity, aldosterone levels, vasopressin levels, and cardiac remodeling and vasoconstriction through AT1receptors on peripheral vessels (conversely, AT2receptors impair cardiac remodeling). This is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial incongestive heart failure.[15]

Angiotensin III

[edit]
Asp | Arg-Val-Tyr-Ile-His-Pro-Phe[clarification needed]

Angiotensin III, along with angiotensin II, is considered an active peptide derived from angiotensinogen.[18]

Angiotensin III has 40% of thepressoractivity of angiotensin II, but 100% of the aldosterone-producing activity. Increasesmean arterial pressure.It is a peptide that is formed by removing an amino acid from angiotensin II byglutamyl aminopeptidaseA, which cleaves the N-terminal Asp residue.[19]

Activation of the AT2 receptor by angiotensin III triggersnatriuresis,while AT2 activation via angiotensin II does not. This natriuretic response via angiotensin III occurs when the AT1 receptor is blocked.[20]

Angiotensin IV

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Arg | Val-Tyr-Ile-His-Pro-Phe[clarification needed]

Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. Angiotensin IV has a wide range of activities in the central nervous system.[21][22]

The exact identity of AT4 receptors has not been established. There is evidence that the AT4 receptor isinsulin-regulated aminopeptidase(IRAP).[23]There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor.[24][25]

Syntheticsmall moleculeanalogues of angiotensin IV with the ability to penetrate throughblood brain barrierhave been developed.[25]

The AT4 site may be involved in memory acquisition and recall, as well as blood flow regulation.[26]Angiotensin IV and its analogs may also benefit spatial memory tasks such as object recognition and avoidance (conditioned and passive avoidance).[27]Studies have also shown that the usual biological effects of angiotensin IV on the body are not affected by common AT2 receptor antagonists such as the hypertension medicationLosartan.[27]

Effects

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See alsoRenin–angiotensin system#Effects

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

Adipic

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Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis... and downregulation of lipolysis."[28]

Cardiovascular

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Angiotensins are potent directvasoconstrictors,constricting arteries and increasing blood pressure. This effect is achieved through activation of theGPCR AT1,which signals through aGq proteinto activate phospholipase C, and subsequently increase intracellular calcium.[29]

Angiotensin II has prothrombotic potential through adhesion and aggregation ofplateletsand stimulation ofPAI-1andPAI-2.[30][31]

Neural

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Angiotensin II increasesthirstsensation (dipsogen) through thearea postremaandsubfornical organof the brain,[32][33][34]decreases the response of thebaroreceptor reflex,increases the desire forsalt,increases secretion ofADHfrom theposterior pituitary,and increases secretion ofACTHfrom theanterior pituitary.[32]Some evidence suggests that it acts on theorganum vasculosum of the lamina terminalis (OVLT)as well.[35]

Adrenal

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Angiotensin II acts on theadrenal cortex,causing it to releasealdosterone,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 themenstrual cycle.

Renal

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Angiotensin II has a direct effect on the proximal tubules to increase Na+reabsorption.It has a complex and variable effect onglomerular filtrationandrenal blood flowdepending 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 maintainglomerular 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 totubuloglomerular 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 includingaldosteronerelease)
Target Action Mechanism[36]
renal artery&
afferent arterioles 		vasoconstriction(weaker) VDCCs→Ca2+influx
efferent arteriole vasoconstriction(stronger) (probably) activateAngiotensin receptor 1→ Activation ofGq→ ↑PLCactivity → ↑IP3andDAG→ activation ofIP3receptorinSR→ ↑intracellular Ca2+
mesangial cells contraction → ↓filtration area
proximal tubule increased Na+reabsorption
  • adjustment ofStarling forcesin peritubular capillaries to favour increased reabsorption
    • efferent and afferent arteriole contraction → decreased hydrostatic pressure in peritubular capillaries
    • efferent arteriole contraction → increased filtration fraction → increased colloid osmotic pressure in peritubular capillaries
  • increasedsodium–hydrogen antiporteractivity
tubuloglomerular feedback increased sensitivity increase inafferent arterioleresponsiveness to signals frommacula densa
medullaryblood flow reduction

See also

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References

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  2. ^abcGRCh38: Ensembl release 89: ENSG00000135744–Ensembl,May 2017
  3. ^abcGRCm38: Ensembl release 89: ENSMUSG00000031980–Ensembl,May 2017
  4. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ^abcdeLu H, Cassis LA, Kooi CW, Daugherty A (July 2016)."Structure and functions of angiotensinogen".Hypertension Research.39(7): 492–500.doi:10.1038/hr.2016.17.PMC4935807.PMID26888118.
  8. ^"AGT - Angiotensinogen precursor - Homo sapiens (Human) - AGT gene & protein".www.uniprot.org.Retrieved2019-12-02.
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  31. ^Gesualdo L, Ranieri E, Monno R, Rossiello MR, Colucci M, Semeraro N, Grandaliano G, Schena FP, Ursi M, Cerullo G (August 1999)."Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells".Kidney International.56(2): 461–70.doi:10.1046/j.1523-1755.1999.00578.x.PMID10432384.
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  36. ^Boulpaep EL, Boron WF (2005).Medical Physiology: a Cellular and Molecular Approach.St. Louis, Mo: Elsevier Saunders. p. 771.ISBN978-1-4160-2328-9.

Further reading

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  • de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (September 2000). "International union of pharmacology. XXIII. The angiotensin II receptors".Pharmacological Reviews.52(3): 415–72.PMID10977869.
  • 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 (August 1993). "Role of angiotensin in the extravascular system".Journal of Human Hypertension.7(Suppl 2): S7-12.PMID8230088.
  • Weir MR, Dzau VJ (December 1999)."The renin-angiotensin-aldosterone system: a specific target for hypertension management".American Journal of Hypertension.12(12 Pt 3): 205S–213S.doi:10.1016/S0895-7061(99)00103-X.PMID10619573.
  • Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (December 2001). "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide".American Journal of Physiology. Heart and Circulatory Physiology.281(6): H2337-65.doi:10.1152/ajpheart.2001.281.6.H2337.PMID11709400.S2CID41296327.
  • Varagic J, Frohlich ED (November 2002). "Local cardiac renin-angiotensin system: hypertension and cardiac failure".Journal of Molecular and Cellular Cardiology.34(11): 1435–42.doi:10.1006/jmcc.2002.2075.PMID12431442.
  • Wolf G (2006). "Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis".Antioxidants & Redox Signaling.7(9–10): 1337–45.doi:10.1089/ars.2005.7.1337.PMID16115039.
  • Cazaubon S, Deshayes F, Couraud PO, Nahmias C (April 2006)."[Endothelin-1, angiotensin II and cancer]".Médecine/Sciences.22(4): 416–22.doi:10.1051/medsci/2006224416.PMID16597412.
  • Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]".Revista de Investigacion Clinica.59(1): 48–56.PMID17569300.
[edit]
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