BRAIN-RENIN ANGITENSIN SYSTEM

BY-ANKIT AGARWAL BMB II SEM 15368003

INTRDUCTIN Brain-Renin angiotensin system is recently known mechanism of maintaining body fluid volume and pressure (B.P)

Is an non-classical RAS.

Works independently as well as cooperatively with classical RAS and RAAS.

Brain RAS plays imp.role in memory consolidation

Plays imp.role in neurodegenerative desease like Alziemers,dementia etc.(provides big room for molecular research)

HISTORY AND DISCOVRIES In 1898,first named as kidney hormone by Tierstedt and Bergman,which then in

1971 was recognised as renin,in RAAS.

EVIDENCES OF INDEPENDENT BRAIN RAS

Felix & Phillips, showed ANG II activated neurons in the brain in SFO(subformical region ),and peptide agonist of ANG II,Saralosin( nonspecific ARA)inhibited ANG II induced activity in those neurons.

Immunochemistry analysis shows ANTIBODY STAINING Renin-Ab - in hypothalamus,pituitary and pineal glands. ANG II-Ab - in hypothalamus and CVO’s.

Actual measurement of Renin & ANG II was done by HPLC & by direct protein assay showed- Higher ANG levels in brain than circulating level of ANG II, suggesting independence of two system.

Then proof of ANG II synthesis in brain is given by Stornetta,he identified glail cell as the site of synthesis of AGT using insitu hybridization mRNA.

These findings clear the air regarding controversies over Brain RAS system.

Comparision between circulating and Brain RAS

Classical RAS Systemic RAS. ANG acts as classical harmone

system. Major effector is ANG II. Renin produced by kidney and

circulates only in systemic circulation.

FUNCTIONS Cardiovascular regulation, Sodium appetite, Blood pressure and volume

regulation by RAS & RAAS.

Non-Classical RAS Brain RAS. ANG acts as Non-classical

neurotransmitter. Major effector are ANG II & ANG

III as well. Renin produced by neurons of

SFO(subformical region of CVO’) FUNCTIONS- Perform all classical functions

along with- Thirst and Vasopressin release, Memory consolidation.

Fig.

FORMATION OF ANGIOTENSIN LIGANDS

Renin release in response to low B.P cleaves angiotensinogen into angiotensin 1(10 aa),

ACE,chymase (serine protese) cleaves his-leu ,dipeptide from the C-terminus and forms angiotensin II (octapeptide),

Glutamyl-aminopeptidase AP-A cleaves Asp from the N- teminus made heptapeptide angiotensin III,

Further, alanyl aminopeptidase AP-N cleaves Arg from N-terminus makes angiotensin IV (hexa peptide),

Carboxypeptidase p & prolyl oligo peptidase cleves phenylalanine from C-terminus and forms angiotensin(3-7)

RECEPTORS AND INHIBITORS 0F BRAIN RAS

RECEPTORS-1) AT1 Receptors- ligand is ANG I & II(works agonistically) AT1 gene located on chromosome 3q,and codes for

40-42 Kda(359 a.a)protein. 2 types of AT1 receptors

AT1A AT1B (Involved in central blood pressure control &

drinking response respectively.

2) AT2 Receptor-

Rsponds to ANG II & III.

AT2 shares 32-34% homology with AT1 receptors & represents protein of 363 aa with 7 transmembrane domains.

AT2 gene is licated on X-chromosome.

Functions - vasodilation, drinking response,anti-proliferative.

3) AT4 Receptors- Known to be identical to insulin regulated aminopeptidase(IRAP). Unlike to AT1 & AT2,AT4 does not responds via G-protein,they

responds via RTK (RECEPTOR TYROSINE KINASE) . Responds to ANG IV, have role in Memory consolidation.

IRAP have- Type II membrane protein,(N-terminal inside) 1025 aa(23 aa in T.M,110 in N-terminus near cytosol,883 in

extracellular domain).

4) Mas Receptor- A,G-protein coupled receptor,. Respond to ANG(1-7), Have role in cardiovascular regulation with ACE2 &ANG(1-7), Also induces to produces NO (Nitric oxide) 7 prostaglandin,also shows role

in diuresis,vasodilations & natriuresis etc.

INHIBITORS1) Inhibitors in formation of angiotensin-a) Glutamyl-aminopeptidase A(AP-A) inhibitor- 3-amino,9-thiobutyl

sulphonate,b) Alanyl-aminopeptidase-N(AP-N) inhibitor- 2-amino pentene,1,5 dithiols.c) Angiotensinogen converting enzyme(ACE) inhibitors-

Captoprils,spiroprils(crosses BBB).2) Inhibitor of ANG receptors- Losartan- AT1-receptor antagonist. Saralasin –Non-specific angiotensin receptor antagonist

INHIBITOR ACTION

Non-classical RAS roleBrain RAS have role in-1) Memory consolidation ,2) Sexual behaviour & reproduction,3) Also have role in – cardiovascular regulation, Sodium appetite, Drinking/thrist

ROLE ON MEMORY CONSOLIDATION Signaling via ANG IV-IRAP, mediated by IP3+DAG activating PKC &

Ca2+.a) Facilitates glucose uptake by prolonging the presence of GLUT4 on the

membrane. So increase glucose uptake in glial cells.b) Ang IV removes the blockage of D2 & D4 dopamine receptors,so they

induce dopamine & acetylcholine resulting in memory development.

ROLE IN CARDIOVASCULAR REGULATION

By maintaining-blood pressure & volume, baroreceptor reflex, Vasopressin release. Cardiovascular control by brain RAS by 2 types Ang II (Octapeptide)

1) Forebrain pathway includes 2) acts on Medulla (AT1-R) CVO’s,PVN,SON(AT1-R) Nucleus of solitary tract(NTS)

Induces Vasopressin release (Acts as nor-epinephrin and activation Baroreptor reflex of alpha adrenergic receptor on PVN ) Incresed B.P.

AP-A inhibitor causes loss of vasopressin release while AP-N inhibitors causes increase vasopressin realese in a dose-dependent manner ,and also AT1-R antagonist ‘Saralasin’,blocks vasopressin release,shows that Ang II & III works via AT1-receptors.

EFFECT ON THIRST REGULATION Angiotensins increase the drinking response(i.e thirst). Mode of action- Ang II

1) Forebrain pathway 2) Hypothalamus. CVO’ organs like SFO & OVLT(oragnum vasculosum of lamina terminalis)

Osmodetector Activation of AT1-R by Ang II & III.(detect plama osmolarity) gives signal to

Insular cortex Drinking response thirst

Thirst signalling requires Phenyalanine at C-terminus of any angiotensin,

Removal of C-terminus Phenylalanine from Ang(1-7)causes complete loss of drinking response .

ACE inhibitors(captopril) reduces drinking response which is induced by Ang I,(inhibit the conversion of Ang I to ANG II).

EFFECT ON SODIUM APPETITE By two ways-

RAAS system serves Brain RAS on Na+ appetite sodium in Na+- deficiency Ang II

Renin + Aldosterone OVLT SFO Ang I Elevates AT1-R in brains. Produces both only water response water & salt response Ang II acts on kidney increased loss of Na+ so appetite Na+ goes to brain & activates sympthatic activity of hypothalamus results in B.P (Hypertension).

SIGNALING TYPE For water intake - Ang II via GPCR (IP3 + Ca2+ mediated) For saline intake - Ang II acts via

P44/42 MAP Kinase cascade.

REFERENCES M.Ian phillips,et al; ‘Brain renin angiotensin in diseases’,keck

graduate institute,Springer-verlag(2008).

John.W.Wright, etal; The brain renin-angiotensin system:a diversity of functions & implications for CNS diseases’,Springer-verlag (2012).

O.Von Bohlen und Halbach, et al; ‘The CNS renin-angiotensin system’, Springer-verlag(2006).