Rening angiotensin system

Question 1

what is renin?

produced where?
its precursor?
actions?

Answer 1

• Aspartic protease with only one known substrate, angiotensinogen.
• Produced by juxtaglomerular granular cells
• Exists in pro-, active and inactive form
• Prorenin the inactive precursor circulates in plasma at 100-fold higher concentrations and can be activated by proteolysis (enzymes , low pH and low temperatures).

Question 2

what is prorenin?
its receptors?
actions?
where is it found?

Answer 2

• Prorenin is usually enzymatically inactive unless activated by cleavage
• Prorenin (and renin) can bind to two distinct receptors
o (pro)renin receptors (ATP6AP2)
o mannose-6-phosphate receptors (M6P/IGF2)
• Prorenin receptors (PRR) are structurally homologous to vacuolar H+ATP-ase (ATP6AP2) but the role of this protein in responses to prorenin is unclear.
• Binding of prorenin to PRR causes
o enzymatic activation of prorenin allowing conversion of angiotensinogen to angiotensin I without cleavage of prorenin
o induces intracellular signalling via MAP kinase pathways.
• Physiological role of PRR unknown
(Pro)renin receptors are present in vascular smooth muscle

Question 3

evidence for local RAS

Answer 3

• Classically plasma renin was thought to account for conversion of angiotensinogen to angiotensin I, but blood pressure correlates poorly with plasma renin activity
• Action of Ang II requires levels that rarely if ever occur in circulating blood
• Venous blood levels of Ang II exceed those expected on the basis of arterial blood levels
• mRNA and protein for renin and angiotensinogen are present in a number of tissues (including heart and vasculature)
• Local tissue production of Ang II is probably an important component of the systemic RAS
• Local RASs have been discovered in organs such as the heart, brain, kidney, pancreas, adipose tissue. Ang II may be able to act as immunomodulator, profibrotic molecule, inhibitor of insulin signalling. Exact role of the local RAS not understood yet.

Question 4

AT2 receptor function?

Answer 4

Functional antagonist of AT1 receptors in some circumstances
• Mediates vasodilation in some blood vessels via bradykinin, endothelial NO and cGMP
• Inhibits renin release by a direct action on JG cells and may protect kidneys from ischaemic damage
• Inhibits growth of cardiac myocytes and perivascular fibrosis in Ang II-infused mice
• Experiments with selective AT2 agonist also indicate a role in CNS function and inflammation

Question 5

AT2 RECEPTORS – A NOVEL TARGET IN STROKE?

Answer 5

Focal ischemic area of mouse brain 24 hours after MCA occlusion in angiotensin II type 2 (AT2) receptor-deficient mice

Question 6

Ang1-7
produced?
actions?

Answer 6

• Mainly produced by the action of ACE2
• Acts on MAS receptor
• Functional antagonist of AT1 receptors in some circumstances
o Vasodilation via bradykinin, prostanoids and endothelial NO
o Inhibits smooth muscle growth in vitro
o Increases diuresis and natriuresis via a tubular action

Question 7

ACE2
is what 
found where
inhibited by classical ACEis?
expression regulated how?

Answer 7

• Carboxypeptidase with 40% identity to ACE.
• Converts Ang II to Ang 1-7 and metabolises various peptides including neurotensin, kinetensin, dynoprhin A but not bradykinin.
• Expressed in heart, kidney, endothelium, smooth muscle and testis.
• Not inhibited by classical ACE inhibitors
• Expression upregulated by inhibition of AT1 receptorsA
• Acts as a receptors for SARS

Question 8

overexpression of ACE2 in mice does what?

how about deficiency of ACE2?

Answer 8

ACE2 overexpression causes cardiac conduction disturbances and sudden death in mice

ACE2-deficient mice show enlarged left and right ventricles but the overall heart size is comparable between both genotypes and there is no evidence for cardiac hypertrophy macroscopically or in isolated cardiomyocytes. The bottom panels show an absence of interstitial fibrosis in ace2-/y mice.

Question 9

ACEI + ARB combination

Answer 9

ACEI + ARB combination
• Combination therapy causes a marked increase in adverse effects, symptomatic hypotension, worsening renal function, and hyperkalemia (Phillips et al., 2007).
• ONTARGET: High risk CVD individuals. Combination therapy resulted in lower BP (2.4/1.4 mmHg vs. ramipril alone), no event benefit but increased adverse effects (Yusuf et al., 2008),

Question 10

renin inhibition

Answer 10

• Aliskiren (released UK Sept 2007) is the first effective oral renin inhibitor
• Binds to the renin S1/S3 pocket and another sub-pocket of the enzyme (S3 to hydrophobic core)
• Lowers BP in mild-moderate hypertension with a safety and tolerability profile comparable to that of irbesartan
• Expensive, role uncertain