DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

726 in the locus p11.4 of the X chromosome and is named ATP6ap2
(ATPase- associated protein). Knockout of the PRR gene is lethal. In
humans, mutations in the PRR gene are associated with mental retardation
and epilepsy, suggesting an important role in cognition, brain
development, and survival (Nguyen and Danser, 2008; Ramser et al.,
2005). Prorenin and renin also bind to mannose-6-phosphate receptor
(M6P), an insulin- like growth factor II receptor that functions as
a clearance receptor.
Binding of (pro)renin to PRR enhances the catalytic activity
of renin by 4-5 fold and induces non- proteolytic activation of
prorenin (Figure 26-3). Bound, activated (pro)renin catalyzes the
conversion of angiotensinogen to AngI, which is subsequently converted
to AngII by ACE located on the cell surface. Locally produced
AngII binds to AT 1
receptors and activates intracellular signaling
events that regulate cell growth, collagen deposition, fibrosis, inflammation,
and apoptosis (Nguyen and Danser, 2008).
The binding of (pro)renin to PRR also induces AngIIindependent
signaling events that include activation of ERK1/2,
p38, tyrosine kinases, TGF-β gene expression, and plasminogen
activator inhibitor type 1 (PAI-1). These signaling pathways are not
blocked by ACE inhibitors or AT 1
receptor antagonists and are
reported to contribute to fibrosis, nephrosis, and organ damage
(Kaneshiro et al., 2007; Nguyen and Danser, 2008; see Figure 26-4).
PRR is abundant in the heart, brain, eye, adrenals, placenta, adipose
tissue, liver, and kidneys. Overexpression of the human PRR in
transgenic animals increases plasma aldosterone levels in the
absence of changes in plasma renin levels and induces hypertension
and nephropathy. Rats overexpressing PRR exhibit increased
expression of COX-2 in the macula densa and develop proteinuria
and glomerulosclerosis that increase with aging (Kaneshiro et al.,
2006; Kaneshiro et al., 2007).
Prorenin is no longer considered the inactive precursor of
renin. Prorenin is capable of activating local (tissue) RAS and AngIIdependent
and independent events that may contribute to organ damage.
Circulating plasma concentrations of prorenin are 10-fold
higher than renin in healthy subjects but are elevated to 100-fold in
diabetic patients and are associated with increased risk of nephropathy,
renal fibrosis, and retinopathy (Danser and Deinum, 2005;
Nguyen and Danser, 2008). The interaction of prorenin with PRR
has become a target for therapeutic interventions.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Alternative Pathways for Angiotensin Biosynthesis.Angiotensinogen
may be converted to AngI or directly to AngII by cathepsin G and tonin.
Other enzymes that convert AngI to AngII include cathepsin G,
chymostatin- sensitive AngII- generating enzyme, and heart chymase.
Chymase contributes to the local tissue conversion of AngI to AngII,
particularly in the heart and kidneys (Paul et al., 2006).
Angiotensin Receptors. AngII and AngIII couple to specific
GPCRs designated AT 1
and AT 2
(de Gasparo et al., 2000). The AT 1
receptor has a 10,000-fold higher affinity for losartan (and related
biphenyl tetrazole derivatives) than the AT 2
receptor. The AT 1
receptor
(359 amino acids) and the AT 2
receptor (363 amino acids) share
34% sequence homology.
Most of the known biological effects of AngII are mediated
by the AT 1
receptor. The AT 1
receptor gene contains a polymorphism
(A- to- C transversion in position 1166) associated with hypertension,
hypertrophic cardiomyopathy, and coronary artery vasoconstriction.
Moreover, the C allele synergizes with the ACE deletion allele with
• Enhanced renin
activity (4–5 times)
• Non-proteolytic
activation of prorenin
Local “tissue”
Ang II production
ERK 1/2, p38,
PAI-1, TGF-β
(Pro)Renin
(Pro)Renin Receptor
Organ Damage
• Ligand binding to
PRR and activation of
intracellular signaling
Effects independent
of Ang II production
ERK 1/2, p38,
PAI-1, TGF-β
• Fibrosis and inflammation of cardiac and vascular tissue
• Nephropathy
• Retinopathy
Figure 26-4. Ang II-dependent and Ang II-independent actions
of prorenin. See text for details.
regard to increased risk of coronary artery disease (Álvarez et al.,
1998). Preeclampsia is associated with the development of agonistic
auto- antibodies against the AT 1
receptor (Wallukat et al., 1999).
Functional roles for the AT 2
receptors are less well defined,
but they may counterbalance many of the effects of the AT 1
receptors
by having antiproliferative, proapoptotic, vasodilatory, natriuretic,
and antihypertensive effects (Jones et al., 2008; Carey et al.,
2001). The AT 2
receptor is distributed widely in fetal tissues, but its
distribution is more restricted in adults. Although the AT 2
receptor
generally is conceptualized as a cardiovascular protective receptor,
its overexpression and activation may contribute to myocyte hypertrophy
and cardiac fibrosis (D’Amore et al., 2005; Ichihara et al.,
2001). Expression of AT 2
receptors is upregulated in cardiovascular
diseases, including heart failure, cardiac fibrosis, and ischemic heart
disease; however, the significance of increased AT 2
receptor expression
is unclear (Jones et al., 2008).