Angiotensin
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Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.
An oligopeptide, angiotensin is a hormone and a dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Angiotensin was isolated in the late 1930s (first named 'angiotonin' or 'hypertensin') and subsequently characterized and synthesized by groups at the Cleveland Clinic and Ciba laboratories.[1]
Precursor and types
Angiotensinogen
Angiotensinogen is an α-2-globulin synthesized 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 the serpin family 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 elongated N-terminus compared 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 as renin substrate. 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 plasma corticosteroid, estrogen, thyroid hormone, 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
- Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...[clarification needed]
Angiotensin I (
Angiotensin I appears to have no direct biological activity and exists solely as a precursor to angiotensin II.
Angiotensin II
- 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 enzyme
ACE is a target of
Other cleavage products of ACE, seven or nine amino acids long, are also known; they have differential affinity for
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 increased
Angiotensin III
- 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 the
Activation of the AT2 receptor by angiotensin III triggers natriuresis, while AT2 activation via angiotensin II does not. This natriuretic response via angiotensin III occurs when the AT1 receptor is blocked.[20]
Angiotensin IV
- 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 is insulin-regulated aminopeptidase (IRAP).[23] There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor.[24][25]
Synthetic
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 medication Losartan.[27]
Effects
- See also Renin–angiotensin system#Effects
Angiotensins II, III and IV have a number of effects throughout the body:
Adipic
Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis ... and downregulation of lipolysis."[28]
Cardiovascular
Angiotensins are potent direct
Angiotensin II has prothrombotic potential through adhesion and aggregation of
Neural
Angiotensin II increases
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+
Target | Action | Mechanism[36] |
---|---|---|
renal artery & afferent arterioles |
vasoconstriction (weaker) | VDCCs → Ca2+ influx
|
efferent arteriole | vasoconstriction (stronger) | (probably) activate IP3 receptor in SR → ↑intracellular Ca2+
|
mesangial cells | contraction → ↓filtration area | |
proximal tubule | increased Na+ reabsorption |
|
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
- Perindopril
- Renin inhibitor
References
- PMID 11751697.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000135744 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031980 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Angiotensin | Hormone Health Network". www.hormone.org. Retrieved 2019-12-02.
- ^ PMID 26888118.
- ^ "AGT - Angiotensinogen precursor - Homo sapiens (Human) - AGT gene & protein". www.uniprot.org. Retrieved 2019-12-02.
- ^ S2CID 29751589.
- PMID 9777817.
- ISBN 978-0-07-146633-2.
- PMID 3306925.
- PMID 31796.
- S2CID 270730.
- ^ ISBN 978-0-12-381462-3.
- ^ Le T (2012). First Aid for the Basic Sciences. Organ Systems. McGraw-Hill. p. 625.
- PMID 29763087.
- PMID 22792446.
- ^ "Angiotensin III". PubChem. NIH. Retrieved 9 May 2019.
- S2CID 37807540.
- S2CID 22816307.
- PMID 19090988.
- PMID 11707427.
- PMID 25649658.
- ^ S2CID 41360989.
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- ^ S2CID 13339562.
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- OCLC 1076268769.)
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: CS1 maint: location missing publisher (link - ISBN 978-1-4160-2328-9.
Further reading
- 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. 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 (August 1993). "Role of angiotensin in the extravascular system". Journal of Human Hypertension. 7 (Suppl 2): S7-12. PMID 8230088.
- 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. PMID 10619573.
- 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. S2CID 41296327.
- 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. PMID 12431442.
- 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. PMID 16115039.
- Cazaubon S, Deshayes F, Couraud PO, Nahmias C (April 2006). "[Endothelin-1, angiotensin II and cancer]". Médecine/Sciences. 22 (4): 416–22. PMID 16597412.
- Ariza AC, Bobadilla NA, Halhali A (2007). "[Endothelin 1 and angiotensin II in preeeclampsia]". Revista de Investigacion Clinica. 59 (1): 48–56. PMID 17569300.
External links
- The MEROPS online database for peptidases and their inhibitors: I04.953 Archived 2019-10-16 at the Wayback Machine
- Angiotensins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human AGT genome location and AGT gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P01019 (Angiotensin) at the PDBe-KB.