Angiotensin

1. The Renin-Angiotensin System &
Neurodegenerative Diseases

2. Talk About…
• Classic RAS
• New hierarchy of RAS
• RAS and neurodegenerative diseases
– Parkinson’s disease
– Dementia

3. Discovery of Renin
• 1898, Tiegerstedt and Bergman, named as a
kidney hormone
“Effects of injecting kidney
extracts in the jugular vein on
blood pressure. Initial decrease
in blood pressure was thought
to be an effect on the heart
because it was absent after
femoral injections.”
Tigerstedt, R. Arch. Physiol. 1898; 8: 223–271

4. Classic RAS

5. RAS Main Components
• Angiotensinogen  Angiotensin II
• Cleaving enzyme
– Renin, ACE
• Receptors
– AT1R, AT2R

6. F1000Research 2017, 6(F1000 Faculty Rev):297
ACE
inhibitor
AngII
receptor
blocker
Renin
inhibitor
AT4

7. Leung PS, The Renin-Angiotensin System: Current Research Progress 69 in The Pancreas, Advances in Experimental
Medicine and Biology. pp 70

8. New RAS Hierarchy
• Humoral (classic, circulating) RAS
– Salt/fluid homeostasis
– Aldosterone/vasocontriction
• Tissue (local) RAS
– Angiotensin II  AT1R
– Inflammation/oxidant stress (ROS, reactive oxygen
species↑)
• Intracellular (intracrine) RAS
– Gene expression

9. J Mol Med. 2008;86(6):715-722

10. Functions of RAS in the Brain
• Blood pressure regulation
• Drinking and food intake
• Central actions on the reproductive system
• Behavior and emotion
• Learning and memory

11. Abiodun OA. Saudi J Biol Sci.2020;27:905–912

12. RAS and Parkinson’s Disease
The American Journal of Medicine (2022) 135:1001−1007

13. Study Design
2001-2013
Newly
Diagnosis of
Hypertension
(n=107,207)
Last OPD Visit Before
2013-12-31
Newly Diagnosis of
Parkinson’s Disease
(n=1,728, 1.7%)
DM
Stroke
CKD
Liver cirrhosis
COPD
ARB
ACEi
Renin i
CCB
Diuretics
Beta blocker
Other anti-HTN
Statin

15. PD, 527, 1.1%
PD, 1,255, 2.2%
HR=0.56 (0.51-0.63)

17. Possible Mechanisms
• Dopaminergic neuron vulnerable to oxidant stress
– Continuous pacing for dopamine output (continuous
calcium ion influx)
– High energy demand
• Angiotensin II blocking
– Reduce NADPH oxidase producing ROS
– Reduce dopaminergic neurons premature apoptosis
– Excessive unbinding angiotensin II activate AT2R, and
AT4R/Mas via angiotensin IV and angiotensin(1-7)

18. Labandeira-García JL. Front Neuroanat. 2014;8:67

19. RAS and Dementia

20. Study Design
2001-2013
Newly Diagnosis of
Hypertension
(n=121,981)
Incident
dementia
(n=964, 2.2%)
DM, Stroke, CKD
Parkinson’s Dz
Charlson comorbidity
index (0, 1, 2-3, >3)
ARB
ACEi, Renin i, CCB,
Diuretics, Beta blocker,
Other anti-HTN, Statin
Propensity score matching, 1:1
(Age, sex, CCI, comorbidities, medications)
ARB +
(n=43,913)
ARB -
(n=43,913)
Incident
dementia
(n=1,551, 3.6%)

22. Dementia, 964, 2.2%
Dementia, 1,551, 3.6%
HR=0.61 (0.56-0.66)

25. Mogi M. Hypertens Res. 2009;32:738-740
Possible Mechanism

26. Conclusions
1. Local RAS taking effects in many organs
2. Brain RAS associate with neurodegenerative
diseases
3. ARB may effectively protect patients from
Parkinson’s diseases and dementia with a
dose-effect manner