Biology:Angiotensin

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Short description: Group of peptide hormones in mammals


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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

Crystal structure of reactive center loop cleaved angiotensinogen via x-ray diffraction

Angiotensinogen is an α-2-globulin synthesized in the liver[2] and is a precursor for angiotensin, but has also been indicated as having many other roles not related to angiotensin peptides.[3] It is a member of the serpin family of proteins, leading to another name: Serpin A8,[4] 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.[5] 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.[3]

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.[3][5] This peptide is 485 amino acids long, and 10 N-terminus amino acids are cleaved when renin acts on it.[3] The first 12 amino acids are the most important for activity.

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

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.[3]

Angiotensin I

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

Angiotensin I (CAS# 11128-99-7), officially called proangiotensin, is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the decapeptide (ten amino acid) (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure (<90mmHg systolic blood pressure[6] ) at the juxtaglomerular cells, dehydration or decreased delivery of Na+ and Cl- to the macula densa.[7] If a reduced NaCl concentration[8] 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 of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts.[9] This, and similar findings obtained in vivo,[10] 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 luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration."[11]

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

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 cells, kidney epithelial cells, and the brain). Angiotensin II acts on the central nervous system to increase vasopressin production, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increases aldosterone secretion; it therefore acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target of 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 an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the Na+/H+ exchanger in the proximal tubules of 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.[12] Hence, ACE inhibitors are major anti-hypertensive drugs.

Other cleavage products of ACE, seven or nine 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. Angiotensin II has a half-life in circulation of around 30 seconds,[13] whereas, in tissue, it may be as long as 15–30 minutes.

Angiotensin II results in increased inotropy, chronotropy, catecholamine (norepinephrine) release, catecholamine sensitivity, aldosterone levels, vasopressin levels, and cardiac remodeling and vasoconstriction through AT1 receptors on peripheral vessels (conversely, AT2 receptors impair cardiac remodeling). This is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial in congestive heart failure.[11]

Angiotensin III

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

Angiotensin III, along with angiotensin II, is considered an active peptide derived from angiotensinogen.[14]

Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases mean arterial pressure. It is a peptide that is formed by removing an amino acid from angiotensin II by glutamyl aminopeptidase A, which cleaves the N-terminal Asp residue.[15]

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.[16]

Angiotensin IV

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

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.[17][18]

The exact identity of AT4 receptors has not been established. There is evidence that the AT4 receptor is insulin-regulated aminopeptidase (IRAP).[19] There is also evidence that angiotensin IV interacts with the HGF system through the c-Met receptor.[20][21]

Synthetic small molecule analogues of angiotensin IV with the ability to penetrate through blood brain barrier have been developed.[21]

The AT4 site may be involved in memory acquisition and recall, as well as blood flow regulation.[22] Angiotensin IV and its analogs may also benefit spatial memory tasks such as object recognition and avoidance (conditioned and passive avoidance).[23] 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.[23]

Effects

See also Renin–angiotensin system

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."[24]

Cardiovascular

Angiotensins are potent direct vasoconstrictors, constricting arteries and increasing blood pressure. This effect is achieved through activation of the GPCR AT1, which signals through a Gq protein to activate phospholipase C, and subsequently increase intracellular calcium.[25]

Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.[26][27]

Neural

Angiotensin II increases thirst sensation (dipsogen) through the area postrema and subfornical organ of the brain,[28][29][30] decreases the response of the baroreceptor reflex, increases the desire for salt, increases secretion of ADH from the posterior pituitary, and increases secretion of ACTH from the anterior pituitary.[28] Some evidence suggests that it acts on the organum vasculosum of the lamina terminalis (OVLT) as well.[31]

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[32]
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 and afferent 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


References

  1. ↑ "History about the discovery of the renin-angiotensin system". Hypertension 38 (6): 1246–9. December 2001. doi:10.1161/hy1201.101214. PMID 11751697. 
  2. ↑ "Angiotensin | Hormone Health Network". https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/angiotensin. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Structure and functions of angiotensinogen". Hypertension Research 39 (7): 492–500. July 2016. doi:10.1038/hr.2016.17. PMID 26888118. 
  4. ↑ "AGT - Angiotensinogen precursor - Homo sapiens (Human) - AGT gene & protein". https://www.uniprot.org/uniprot/P01019. 
  5. ↑ 5.0 5.1 "Angiotensinogen cleavage by renin: importance of a structurally constrained N-terminus". FEBS Letters 436 (2): 267–270. October 1998. doi:10.1016/S0014-5793(98)01145-4. PMID 9781693. 
  6. ↑ "Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents". JAMA 280 (13): 1168–72. October 1998. doi:10.1001/jama.280.13.1168. PMID 9777817. 
  7. ↑ "Chapter 336: Disorders of the Adrenal Cortex". Harrison's principles of internal medicine. McGraw-Hill Medical. 2008. ISBN 978-0-07-146633-2. 
  8. ↑ "Direct demonstration of macula densa-mediated renin secretion". Science 237 (4822): 1618–1620. 1987. doi:10.1126/science.3306925. PMID 3306925. Bibcode: 1987Sci...237.1618S. 
  9. ↑ "Importance of chloride for acute inhibition of renin by sodium chloride". The American Journal of Physiology 235 (5): F444–50. November 1978. doi:10.1152/ajprenal.1978.235.5.F444. PMID 31796. 
  10. ↑ "Adenosine as a mediator of macula densa-dependent inhibition of renin secretion". American Journal of Physiology. Renal Physiology 290 (5): F1016–23. May 2006. doi:10.1152/ajprenal.00367.2005. PMID 16303857. 
  11. ↑ 11.0 11.1 "Function of the Juxtaglomerular Apparatus". Seldin and Giebisch's the Kidney (Fifth ed.). Academic Press. 2013. pp. 757–801. doi:10.1016/B978-0-12-381462-3.00023-9. ISBN 978-0-12-381462-3. 
  12. ↑ First Aid for the Basic Sciences. Organ Systems. McGraw-Hill. 2012. p. 625. 
  13. ↑ Patel, Preeti; Sanghavi, Devang; Morris, Deborah L.; Kahwaji, Chadi I. (2023). "Angiotensin II". StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK499912/. 
  14. ↑ "Focus on Brain Angiotensin III and Aminopeptidase A in the Control of Hypertension". International Journal of Hypertension 2012: 124758. 2012. doi:10.1155/2012/124758. PMID 22792446. 
  15. ↑ "Angiotensin III". NIH. https://pubchem.ncbi.nlm.nih.gov/compound/angiotensin_iii. 
  16. ↑ "Renal angiotensin type 2 receptors mediate natriuresis via angiotensin III in the angiotensin II type 1 receptor-blocked rat". Hypertension 47 (3): 537–544. March 2006. doi:10.1161/01.HYP.0000196950.48596.21. PMID 16380540. 
  17. ↑ "The angiotensin IV/AT4 receptor". Cellular and Molecular Life Sciences 61 (21): 2728–2737. November 2004. doi:10.1007/s00018-004-4246-1. PMID 15549174. 
  18. ↑ "Cognitive-enhancing effects of angiotensin IV". BMC Neuroscience 9 (Suppl 2): S15. December 2008. doi:10.1186/1471-2202-9-S2-S15. PMID 19090988. 
  19. ↑ "Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase". The Journal of Biological Chemistry 276 (52): 48623–6. December 2001. doi:10.1074/jbc.C100512200. PMID 11707427. 
  20. ↑ "The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease". Journal of Alzheimer's Disease 45 (4): 985–1000. 2015-01-01. doi:10.3233/JAD-142814. PMID 25649658. 
  21. ↑ 21.0 21.1 "The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases". Progress in Neurobiology 125: 26–46. February 2015. doi:10.1016/j.pneurobio.2014.11.004. PMID 25455861. 
  22. ↑ "The angiotensin IV system: functional implications". Frontiers in Neuroendocrinology 16 (1): 23–52. January 1995. doi:10.1006/frne.1995.1002. PMID 7768321. 
  23. ↑ 23.0 23.1 "Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies". Neuroscience and Biobehavioral Reviews 92: 209–225. September 2018. doi:10.1016/j.neubiorev.2018.05.005. PMID 29733881. 
  24. ↑ "Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity". Kidney International 79 (2): 162–8. January 2011. doi:10.1038/ki.2010.391. PMID 20944545. 
  25. ↑ "Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined". Circulation Research 93 (11): 1015–7. November 2003. doi:10.1161/01.RES.0000105920.33926.60. PMID 14645130. 
  26. ↑ "Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture". Hypertension 37 (5): 1336–40. May 2001. doi:10.1161/01.HYP.37.5.1336. PMID 11358950. 
  27. ↑ "Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells". Kidney International 56 (2): 461–70. August 1999. doi:10.1046/j.1523-1755.1999.00578.x. PMID 10432384. 
  28. ↑ 28.0 28.1 "Sensory circumventricular organs and brain homeostatic pathways". FASEB Journal 7 (8): 678–86. May 1993. doi:10.1096/fasebj.7.8.8500693. PMID 8500693. 
  29. ↑ "High metabolic activity in the dorsal vagal complex of Brattleboro rats". Brain Research 505 (2): 316–20. December 1989. doi:10.1016/0006-8993(89)91459-5. PMID 2598049. 
  30. ↑ "Metabolic activation of efferent pathways from the rat area postrema". The American Journal of Physiology 258 (3 Pt 2): R788-97. March 1990. doi:10.1152/ajpregu.1990.258.3.R788. PMID 2316724. 
  31. ↑ Ganong's review of medical physiology (26th ed.). New York. 2019. pp. 304. ISBN 978-1260122404. OCLC 1076268769. https://www.worldcat.org/oclc/1076268769. 
  32. ↑ Medical Physiology: a Cellular and Molecular Approach. St. Louis, Mo: Elsevier Saunders. 2005. pp. 771. ISBN 978-1-4160-2328-9. 

Further reading

  • "International union of pharmacology. XXIII. The angiotensin II receptors". Pharmacological Reviews 52 (3): 415–72. September 2000. 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
  • "Role of angiotensin in the extravascular system". Journal of Human Hypertension 7 (Suppl 2): S7-12. August 1993. PMID 8230088. 
  • "The renin-angiotensin-aldosterone system: a specific target for hypertension management". American Journal of Hypertension 12 (12 Pt 3): 205S–213S. December 1999. doi:10.1016/S0895-7061(99)00103-X. PMID 10619573. 
  • "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide". American Journal of Physiology. Heart and Circulatory Physiology 281 (6): H2337-65. December 2001. doi:10.1152/ajpheart.2001.281.6.H2337. PMID 11709400. 
  • "Local cardiac renin-angiotensin system: hypertension and cardiac failure". Journal of Molecular and Cellular Cardiology 34 (11): 1435–42. November 2002. doi:10.1006/jmcc.2002.2075. PMID 12431442. 
  • "Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis". Antioxidants & Redox Signaling 7 (9–10): 1337–45. 2006. doi:10.1089/ars.2005.7.1337. PMID 16115039. 
  • "[Endothelin-1, angiotensin II and cancer]". Médecine/Sciences 22 (4): 416–22. April 2006. doi:10.1051/medsci/2006224416. PMID 16597412. 
  • "[Endothelin 1 and angiotensin II in preeeclampsia]". Revista de Investigacion Clinica 59 (1): 48–56. 2007. PMID 17569300. 

External links



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