introduction to the independent brain RAS

1. BRAIN-RENIN
ANGITENSIN SYSTEM
BY-ANKIT AGARWAL
BMB II SEM
15368003

2. INTRDUCTIN
 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)

3. 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.

4.  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.

5. 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.

7. Fig.

8. 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)

11. 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.

13. 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.

14. 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).

16. 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.
INHIBITORS
1) 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

17. INHIBITOR ACTION

18. Non-classical RAS role
Brain 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.

19. 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.

20.  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

21.  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).

22. 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).

23. SIGNALING TYPE
 For water intake - Ang II via GPCR
(IP3 + Ca2+ mediated)
 For saline intake - Ang II acts via P44/42
MAP Kinase cascade.

24. 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).