Cardio Diabetes Master Class
October 15-17, 2010, Dublin
Targeting the Renin Angiotensin System:
Past, Present and Future
Slide lecture prepared and held by:
Thomas Unger, MD
Charité
University Medicine Berlin
Germany
P HYS I C IAN S ’ A CAD EMY
FOR
C A R D I O VA S C U LA R E D U C AT I O N
The Renin-Angiotensin-System
Angiotensinogen
Renin
Angiotensin I
Ang-(1-9)
ACE2
ACE
Angiotensin II
NEP
Ang-(1-7)
Mas-R
ACE
Ang-(1-5)
ANG II
ANG II
AT1
AT2
CCR
Angiotensin effects on the nephron
Angiotensin II
+
+ +
+
Pglom 
-
Aldosterone
+
Proximal Na+reabsorption 
Na+-reabsorption 
CCR
RAS in cardiovascular pathology
Risk factors: diabetes, obesity, smoking, age
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
Atherosclerosis
Apoptosis
Arrhythmia
LVH
Heart failure
Fibrosis
MI
Vascular
disease
Hypertension
Pro-thrombotic state
Angiotensin II via AT1
Stroke
Death
Cognitive
dysfunction
Decreased GFR
Proteinuria/albuminuria
Renal failure
Glomerulosclerosis
Adapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S–156S
CCR
Drugs inhibiting the renin-angiotensin-aldosterone system
Angiotensinogen
Renin
inhibitors
Renin
ACE
inhibitors ACE
Aldosterone Aldosterone
antagonists
AT1 Receptor Blockers
+
ANG I
Bradykinin
ACE
inhibitors ACE
ANG II
ANG II
ANG II
AT1
AT2
CCR
CCR
LIFE study: Greater regression of LVH with ARB
(losartan) than with β-blocker (atenolol)
Change from baseline (%) in LVH determined by
electrocardiography
0
16
-2
14
-4
-6
12
4.4%
10
-8
9.0%
-10
-12
8
6
10.2%
p < 0.0001
4
-14
-16
Atenolol (n=4588)
Losartan (n=4605)
-18
15.3%
Dahlöf B et al. Lancet 2002
Composite of CV
Death,
stroke and MI
Atenolol
(n=4588)
Losartan
(n=4605)
Adjusted Risk Reduction:
13.0%, p = 0.021
0
p < 0.0001
Cornell
Voltage-Duration
Product
2
Proportion of patients
with first event (%)
0 6 12 18 24 30 36 42 48 54 60 66
Sokolow-Lyon
Voltage
Time (months)
Discontinuation as a result of all adverse events, drug-related adverse events, and
serious and serious and drug-related adverse events were significantly less
common
CCR
in losartan patients than atenolol patients.
ANG II: Progression of Chronic Renal Disease
Renal disease
ANG II
AT1 RA
ANG II
Angiotensinogen
Fibroblasts
Proliferation
Differentation
NF- kB
Profibrotic
Cytokines
Matrix
Fibrosis
Klahr et al., 2000
TNF-a
Tubule Cells
ANG II
ANG II
Oxidative Stress
Direct Cytotoxicity
Vasoconstriction
Inflammation
Growth Effect
Chemoattractants
Adhesion proteins
Inflammation
CCR
Comparison of IDNT- and RENAAL-Results
Relative Change vs
Amlodipine-based or Control Therapy (%)
IDNT
Primary Endpoint
RENAAL
0
-5
- 10
- 15
- 16 %
- 20
- 20 %
- 25
- 30
- 23 %
Irbesartan
vs Amlodipine
Lewis E.J. et al., N. Engl. J. Med. 2001; 345: 851-60 ;
Brenner B.M. et al., N. Engl. J. Med. 2001; 345: 861-9
Losartan
vs Control
NNT = 15
vs Control
CCR
AT1R-Antagonism (Telmisartan) and PPAR
Schupp et al Circulation 2004
Benson et al Hypertension 2004
Clasen et al Hypertension 2005
Zhao Yi et al J Neurochem 2005
Schupp et al Diabetes 2005
Schupp et al Hypertension 2006
Angiotensin II
ARB
Cell membrane
AT1
AT2
Nuclear membrane
Anti-hypertensive
Anti-inflammatory
Anti-atherosclerotic
Anti-diabetic
L
PPARs
PPRE
5’
RA
p300
RXR
Gene
3’
CCR
Angiotensin-Receptors
ANG II
ANG II
AT1
AT2
 Vasoconstriction
 Na+-Retention
 Aldosterone-Release
 Vasodilation (?)
 (Neuro-)regeneration
 Proliferation
 Fibrosis
 Inflammation
 Anti-Proliferation
 Anti-Fibrosis
 Anti-Inflammation
CCR
Endothelial Cells
AT2 transfection in vivo
control
Ang II
control
neointima
injury
Ang II+losartan
Ang II+PD123177
Stoll M et al. J Clin Invest 1995
injury + AT2
transfection
Nakajima M et al. Proc Natl Acad Sci 1995
CCR
Angiotensin AT2 Receptor
The Key: Pharmacological
Stimulation of a natural
protective system
Physiology/Pathophysiology:
Endogenous tissue-protective
system
C 21II
ANG
Compound 21
AT2
• NO Production
• Vasodilation (?)
•
•
•
•
•
Anti-Proliferation
Anti-Fibrosis
Anti-Inflammation
(Neuro-)regeneration
Differentiation
CCR
Compound 21: a biased agonist ?
R
compound 21
R*1
AT2R
Cardiomyocyte diameter
Kardiomyozytendurchmesser (µm)
24
SHP-1 ATBP
anti-hypertrophic and
anti-inflammatory
responses
120
**
•••
18
12
6
0
Ko
100
STN
STN+C21
IL6-RLA (%)
80
60
40
20
0
control
TNFa
TNFa
+ C21
TNFa + HC
CCR
The Two Sides of Renin Receptor Stimulation
angiotensin IIdependent
effects
(pro)renin
angiotensin I
RERBs
4-5 fold (renin)
angiotensinogen
RER
cell membrane
PLZF
nuclear
membrane
angiotensin IIindependent
effects
(-) RER
-
RER-promoter
PI3K-85α-promoter
Schefe et al Circ Res 2006
Schefe et al J Hypertension 2008
end-organ damage ?
(+) cell number
(+) proliferation
(-) apoptosis
CCR