103pathways, which, although still incompletely elucidated, implicate angiotensin II as
activating factor for an extracellular signal-regulated kinase (ERK1/2) [ 105 ]. On the
other hand, excessive angiotensin II signaling leads to high levels of intracellular
calcium recruitment in fibroblasts, though recent research has shown that this event
is diminished by insulin in insulin-sensitive individuals [ 106 ]. Hence, since the
insulin resistance appears to be related to a subnormal Galpha(i2)-mediated signal
transduction, it could provide a pathway for regulation of angiotensin II signaling
pathway.
Protective Pathways
Several studies have reported protective roles for some of the elements described
above. Thus, the AT1R is one of the main characters of the ACE-angiotensin
II-AT1R pathway, which functions as a counter-regulatory axis for RAAS. It has
been suggested that AT1R functions as stimulatory factor on sodium reabsorption
as they are related to the increased expression of specific tubular sodium transport-
ers [ 107 ], while AT2R has the reverse action, increasing natriuresis and lowering
blood pressure through an autocrine cascade including bradykinin, nitric oxide, and
cyclic GMP and controlling vasodilator prostaglandins [ 108 ]. It seems that the
interaction between these renal pathways bears significance for the increase of
long-term effective management of blood pressure, with AT2R having an opposite
protective role to that of AT1R. Moreover, experimental studies have shown that
AT2R stimulation mediates vasodilatory and natriuretic effects, increasing renal
function especially in women, which indicates a potential therapeutic target for
cardiovascular disease [ 109 ].
Several studies have attributed a protective role for plasma angiotensin 1–7 in the
vascular smooth muscle, through reversal of vascular proliferation [ 110 ], as well as
a role in regulation of metabolic pathways related to cell death and survival in
human endothelial cells [ 111 ]. Furthermore, it seems that the protective signaling of
angiotensin 1–7 against diastolic dysfunction is independent of blood pressure regu-
lation [ 112 ] and is mediated through activated pathways contributing to Ca2+ han-
dling, hypertrophy, and survival. Moreover, another counter-regulatory axis for
RAAS, the ACE-angiotensin 1–7-Mas receptor pathway, plays a significant role in
cardiovascular repair [ 113 ], with antihypertrophic and antifibrotic actions [ 114 ],
through stimulation of CD34+ stem/progenitor cells, which are cardiovascular pro-
tective [ 115 ]. Although the renal protective action of this peptide hormone is
reported, especially against endothelial dysfunction or angiotensin II-stimulated
tubular damage, its involvement in glomerular function is not yet fully elucidated
[ 116 ]. Conversely, it appears that the involvement of angiotensin 1–7 in blood pres-
sure regulation is mostly indirect, through interaction of bradykinin and nitric oxide
signaling [ 114 ], while there are studies which suggest it could act as an endogenous
ACE inhibitor [ 117 ], given increased levels of angiotensin 1–7 during ACE-I admin-
istration [ 118 ].
7 Pathophysiological Insights in Resistant Hypertension