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Renin–angiotensin system

Renin-angiotensin-aldosterone system

Angiotensinogen

ReninAngiotensin I

Angio tensin II

Liver

Kidneys

AdrenalsAldosterone

+Thirst

+Antidiuretic hormone

-

Na excr etio n

H O exc reti on 2

--

+

Vasoconstriction ofblood vessels

Hypothalamus of brain

Pituitary glandCorticotropin-releasing hormone

ACTH

K excretion + +

High plasma K +

+Effective circulating volume

+Extracellular fluid volume

Bloodpressure

+

-

+

+

ACEin lungs

Anatomical diagram of RAAS [1]

The renin–angiotensin system (RAS ) or the renin–angiotensin–aldosterone system (RAAS ) is a hormonesystem that regulates blood pressure and water ( uid) bal-ance.

When renal blood ow is reduced, juxtaglomerular cellsin the kidneys convert the prorenin already present inthe blood into renin and secrete it directly into circu-lation. Plasma renin then carries out the conversion ofangiotensinogen released by the liver to angiotensin I .[2]

Angiotensin I is subsequently converted to angiotensin IIby the enzyme angiotensin-converting enzyme found inthe lungs. Angiotensin II is a potent vaso-active pep-tide that causes blood vessels to constrict, resulting inincreased blood pressure. [3] Angiotensin II also stimu-lates the secretion of the hormone aldosterone [3] from theadrenal cortex . Aldosterone causes the tubules of the kid-neys to increase the reabsorption of sodium and waterinto the blood. This increases the volume of uid in thebody, which also increases blood pressure.

If the renin–angiotensin–aldosterone system is abnor-mally active, blood pressure will be too high. There are

many drugs that interrupt different steps in this systemto lower blood pressure. These drugs are one of themain ways to control high blood pressure ( hypertension ),

heart failure , kidney failure , and harmful effects ofdiabetes .[4][5]

1 Activation

RAAS schematic

The system can be activated when there is a loss ofblood volume or a drop in blood pressure (such as inhemorrhage or dehydration ). This loss of pressure is in-

terpreted by baroreceptors in the carotid sinus . In alter-native fashion, a decrease in the ltrate NaCl concentra-tion and/or decreased ltrate ow rate will stimulate themacula densa to signal the juxtaglomerular cells to releaserenin.

1. If the perfusion of the juxtaglomerular apparatusin the kidney’s macula densa decreases, then thejuxtaglomerular cells (granular cells, modied peri-cytes in the glomerular capillary) release the enzymerenin .

2. Renin cleaves a zymogen , an inactive peptide , calledangiotensinogen , converting it into angiotensin I .

3. Angiotensin I is then converted to angiotensin II byangiotensin-converting enzyme (ACE), [6] which isthought to be found mainly in lung capillaries . Onestudy in 1992 found ACE in all blood vessel en-dothelial cells. [7]

4. Angiotensin II is the major bioactive product of therenin-angiotensin system, binding to receptors onintraglomerular mesangial cells , causing these cellsto contract along with the blood vessels surroundingthem and causing the release of aldosterone from the

zona glomerulosa in the adrenal cortex . AngiotensinII acts as an endocrine , autocrine /paracrine , andintracrine hormone.

1

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2 3 LOCAL RENIN-ANGIOTENSIN SYSTEMS

2 Cardiovascular effects

Further reading: Angiotensin#Effects and Aldosterone#Function

It is believed that angiotensin I may have some minor ac-tivity, but angiotensin II is the major bio-active product.Angiotensin II has a variety of effects on the body:

• Throughout the body, it is a potent vasoconstrictorof arterioles .

• In the kidneys, AII constricts glomerular arterioles,having a greater effect on efferent arterioles thanafferent. As with most other capillary beds in thebody, the constriction of afferent arterioles increasesthe arteriolar resistance, raising systemic arterialblood pressure and decreasing the blood ow. How-ever, the kidneys must continue to lter enoughblood despite this drop in blood ow, necessitatingmechanisms to keep glomerular blood pressure up.To do this, angiotensin II constricts efferent arteri-oles, which forces blood to build up in the glomeru-lus, increasing glomerular pressure. The glomerularltration rate (GFR) is thus maintained, and bloodltration can continue despite lowered overall kid-ney blood ow. Because the ltration fraction has

increased, there is less plasma uid in the down-stream peritubular capillaries. This in turn leads toa decreased hydrostatic pressure and increased on-cotic pressure (due to unltered plasma proteins) inthe peritubular capillaries. The effect of decreasedhydrostatic pressure and increased oncotic pressurein the peritubular capillaries will facilitate increasedreabsorption of tubular uid.

• Angiotensin II decreases medullary blood owthrough the vasa recta. This decreases the washoutof NaCl and urea in the kidney medullary space.Thus, higher concentrations of NaCl and urea in the

medulla facilitate increased absorption of tubularuid. Furthermore, increased reabsorption of uidinto the medulla will increase passive reabsorption

of sodium along the thick ascending limb of the loopof Henle.

• Angiotensin II stimulates Na+/H+exchangers located on the apical membranes (faces

the tubular lumen) of cells in the proximal tubuleand thick ascending limb of the loop of Henle inaddition to Na+channels in the collecting ducts. This will ultimatelylead to increased sodium reabsorption

• Angiotensin II stimulates the hypertrophy of renaltubule cells, leading to further sodium reabsorption.

• In the adrenal cortex , it acts to cause the releaseof aldosterone . Aldosterone acts on the tubules(e.g., the distal convoluted tubules and the corticalcollecting ducts ) in the kidneys, causing them to re-absorb more sodium and water from the urine. Thisincreases blood volume and, therefore, increasesblood pressure. In exchange for the reabsorbingof sodium to blood, potassium is secreted into thetubules, becomes part of urine and is excreted.

• Release of anti-diuretic hormone (ADH), [3] alsocalled vasopressin – ADH is made in the hypotha-lamus and released from the posterior pituitarygland . As its name suggests, it also exhibits vaso-constrictive properties, but its main course of actionis to stimulate reabsorption of water in the kidneys.

ADH also acts on the central nervous system to in-crease an individual’s appetite for salt, and to stim-ulate the sensation of thirst .

These effects directly act together to increase blood pres-sure and are opposed by atrial natriuretic peptide (ANP).

3 Local renin-angiotensin systems

Locally expressed renin-angiotensin systems have beenfound in a number of tissues, including the kidneys ,adrenal glands , the heart , vasculature and nervous sys-tem , and have a variety of functions, including local car-diovascular regulation, in association or independentlyof the systemic renin-angiotensin system, as well asnon-cardiovascular functions. [6][8][9] Outside the kidneys,renin is predominantly picked up from the circulationbut may be secreted locally in some tissues; its pre-cursor prorenin is highly expressed in tissues and morethan half of circulating prorenin is of extrarenal ori-gin, but its physiological role besides serving as pre-cursor to renin is still unclear. [10] Outside the liver, an-giotensinogen is picked up from the circulation or ex-

pressed locally in some tissues; with renin they form an-giotensin I, and locally expressed angiotensin-convertingenzyme , chymase or other enzymes can transform it into

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3

angiotensin II. [10][11][12] This process can be intracellularor interstitial. [6]

In the adrenal glands, it is likely involved in the paracrineregulation of aldosterone secretion, in the heart and vas-culature, it may be involved in remodeling or vascular

tone, and in the brain where it is largely independent ofthe circulatory RAS, it may be involved in local bloodpressure regulation. [6][9][13] In addition, both the centraland peripheral nervous systems can use angiotensin forsympathetic neurotransmision. [14] Other places of ex-pression include the reproductive system, the skin and di-gestive organs. Medications aimed at the systemic systemmay affect the expression of those local systems, bene-cially or adversely. [6]

4 Fetal renin-angiotensin system

In the fetus , the renin-angiotensin system is predomi-nantly a sodium-losing system, as angiotensin II has littleor no effect on aldosterone levels. Renin levels are highin the fetus, while angiotensin II levels are signicantlylower; this is due to the limited pulmonary blood ow,preventing ACE (found predominantly in the pulmonarycirculation) from having its maximum effect.

5 Clinical signicance

•

Inhibitors of angiotensin-converting enzyme (ACEinhibitors) are often used to reduce the formation ofthe more potent angiotensin II. Captopril is an ex-ample of an ACE inhibitor. ACE cleaves a numberof other peptides, and in this capacity is an impor-tant regulator of the kinin–kallikrein system , as suchblocking ACE can lead to side effects.

• Angiotensin receptor blockers (ARBs) can be usedto prevent angiotensin II from acting on angiotensinreceptors .

• Direct renin inhibitors can also be used forhypertension. [15] The drugs that inhibit renin arealiskiren [16] and the investigational remikiren .[17]

• Vaccines against angiotensin II, for exampleCYT006-AngQb , have been investigated. [18][19]

6 See also

• Renin inhibitor

• ACE inhibitor

• Angiotensin II receptor antagonist

• Discovery and development of angiotensin re-ceptor blockers

7 References

[1] Boron, Walter F. (2003). “Integration of Salt andWater Balance (pp. 866–7); The Adrenal Gland (p.1059)". Medical Physiology: A Cellular And Molecular Approaoch . Elsevier/Saunders. ISBN 1-4160-2328-3 .

[2] Kumar, Abbas; Fausto, Aster (2010). “11”. Pathologic Basis of Disease (8th ed.). Saunders Elsevier. p. 493.ISBN 978-1-4160-3121-5 .

[3] Yee AH, Burns JD, Wijdicks EF (April 2010). “Cere-bral salt wasting: pathophysiology, diagnosis, and treat-ment”. Neurosurg Clin N Am 21 (2): 339–52.doi:10.1016/j.nec.2009.10.011 . PMID 20380974 .

[4] “High Blood Pressure: Heart and Blood Vessel Disor-ders” . Merck Manual Home Edition .

[5] Solomon, Scott D; Anavekar, Nagesh (2005). “A Brief

Overview of Inhibition of the Renin-Angiotensin System:Emphasis on Blockade of the Angiotensin II Type-1 Re-ceptor” . Medscape Cardiology 9 (2).

[6] Paul M, Poyan Mehr A, Kreutz R (July 2006).“Physiology of local renin-angiotensin systems” . Physiol.Rev. 86 (3): 747–803. doi:10.1152/physrev.00036.2005 .PMID 16816138 .

[7] Rogerson FM, Chai SY, Schlawe I, Murray WK, Mar-ley PD, Mendelsohn FA (July 1992). “Presence ofangiotensin converting enzyme in the adventitia oflarge blood vessels”. J. Hypertens. 10 (7): 615–20. doi:10.1097/00004872-199207000-00003 . PMID

1321187 .

[8] Kobori, H.; Nangaku, M.; Navar, L. G.; Nishiyama, A.(1 September 2007). “The Intrarenal Renin-AngiotensinSystem: From Physiology to the Pathobiology of Hyper-tension and Kidney Disease” . Pharmacological Reviews 59 (3): 251–287. doi :10.1124/pr.59.3.3 . PMC 2034302 .PMID 17878513 .

[9] Ehrhart-Bornstein, M; Hinson, JP; Bornstein, SR;Scherbaum, WA; Vinson, GP (April 1998). “Intraadrenalinteractions in the regulation of adrenocorticalsteroidogenesis” . Endocrine reviews 19 (2): 101–43. doi:10.1210/er.19.2.101 . PMID 9570034 .

[10] Nguyen, G (March 2011). “Renin, (pro)renin and re-ceptor: an update” . Clinical science (London, England : 1979) 120 (5): 169–78. doi:10.1042/CS20100432 .PMID 21087212 .

[11] Kumar, R; Singh, VP; Baker, KM (March 2008).“The intracellular renin-angiotensin system: implica-tions in cardiovascular remodeling”. Current opin-ion in nephrology and hypertension 17 (2): 168–73. doi:10.1097/MNH.0b013e3282f521a8 . PMID18277150 .

[12] Kumar, R; Singh, VP; Baker, KM (April 2009).“The intracellular renin-angiotensin system in theheart”. Current hypertension reports 11 (2): 104–10.doi:10.1007/s11906-009-0020-y . PMID 19278599 .

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4 8 EXTERNAL LINKS

[13] McKinley, MJ; Albiston, AL; Allen, AM; Mathai, ML;May, CN; McAllen, RM; Oldeld, BJ; Mendelsohn, FA;Chai, SY (June 2003). “The brain renin-angiotensin sys-tem: location and physiological roles”. The international journal of biochemistry & cell biology 35 (6): 901–18.doi:10.1016/S1357-2725(02)00306-0 . PMID 12676175 .

[14] Patil J, Heiniger E, Schaffner T, Mühlemann O, Imbo-den H (April 2008). “Angiotensinergic neurons in sym-pathetic coeliac ganglia innervating rat and human mesen-teric resistance blood vessels”. Regul. Pept. 147 (1–3): 82–7. doi:10.1016/j.regpep.2008.01.006 . PMID18308407 .

[15] Presentation on Direct Renin Inhibitors as Antihyperten-sive Drugs

[16] Gradman A, Schmieder R, Lins R, Nussberger J, Chi-angs Y, Bedigian M (2005). “Aliskiren, a novel orallyeffective renin inhibitor, provides dose-dependent an-tihypertensive efficacy and placebo-like tolerability inhypertensive patients”. Circulation 111 (8): 1012–8. doi:10.1161/01.CIR.0000156466.02908.ED . PMID15723979 .

[17] Richter WF, Whitby BR, Chou RC (1996). “Distributionof remikiren, a potent orally active inhibitor of humanrenin, in laboratory animals”. Xenobiotica 26 (3): 243–54. doi :10.3109/00498259609046705 . PMID 8730917 .

[18] Tissot AC, Maurer P, Nussberger J, Sabat R, Pster T,Ignatenko S, Volk HD, Stocker H, Müller P, JenningsGT, Wagner F, Bachmann MF (March 2008). “Effectof immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind,randomised, placebo-controlled phase IIa study” . Lancet 371 (9615): 821–7. doi :10.1016/S0140-6736(08)60381-5. PMID 18328929 .

[19] Brown, MJ (2009). “Success and failure of vac-cines against renin-angiotensin system compo-nents”. Nature reviews. Cardiology 6 (10): 639–47.doi:10.1038/nrcardio.2009.156 . PMID 19707182 .

• Banic A, Sigurdsson GH, Wheatley AM (1993).“Inuence of age on the cardiovascular responseduring graded haemorrhage in anaesthetizedrats”. Res Exp Med (Berl) 193 (5): 315–21.doi:10.1007/BF02576239 . PMID 8278677 .

8 External links

• Renin-Angiotensin System at the US NationalLibrary of Medicine Medical Subject Headings(MeSH)

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