99and assay methodology are accumulating, and new treatment approaches are also
elaborated [ 56 ].
Therapeutic correlation Increased plasma aldosterone levels and primary aldoste-
ronism are associated with the absence of aldosterone escape phenomenon in the
context of long-term treatment with ACE-I or ARB, which provides the opportunity
to use a first-line therapy with mineralocorticoid receptor antagonists [ 57 ].
Conversely, for resistant hypertension associated with normal plasma aldosterone
levels, ARB or ACE-I may be used as first-line therapy with the introduction of an
MR antagonist as an add-on agent [ 58 ].
Furthermore, it has been proved that decreased expression of regulators of G pro-
tein signaling 2 (RGS2) contributes, together with increased plasma aldosterone lev-
els and high aldosterone/renin ratio, to the development of resistant hypertension [ 59 ].
It has also been suggested that increased levels of corticotropin could determine the
increase in aldosterone, as well as in brain and atrial natriuretic peptide levels [ 60 ].
Therapeutic correlation Experimental studies have shown that the subacute modi-
fications in RAAS activity during ACE-I treatment, reflected in increases in the
urinary aldosterone/creatinine ratio, indicate an incomplete blockade of the system
and the presence of escape mechanisms, which could prove useful in evaluation of
effectiveness of therapy and a better management of the disease [ 61 ].
Renin and Prorenin
Within the current trend of optimization of RAAS blockade in RH, a special interest is
dedicated to the prorenin receptor (PRR). This component of the RAAS system is located
in the kidneys, within mesangial cells, renal arterioles, and distal nephron segments, and
has four distinct functions: (1) To bind renin and prorenin in the production of angiotensin
I, increasing renin catalytic activity and activating prorenin. (2) To activate intracellular
signals when a ligand binds to PRR, upregulating the expression of profibrotic genes. (3)
To contribute to the functions of vacuolar proton ATPase. (4) To take part in the Wnt
signaling pathways [ 62 ], which play a critical role in adult and embryonic stem cell biol-
ogy, embryonic development, and various diseases such as cancer [ 63 ].
Additionally, given that the stimulatory effects of prorenin on microglial acti-
vation and production of proinflammatory cytokines have been ascertained, the
PRR could also be involved in the development of RAAS-induced neurogenic
hypertension [ 64 ].
While results of animal studies did not clearly ascertain the significance of PRR
in hypertension or in organ damage, human studies indicated that there exists a cor-
relation between a polymorphism of the PRR gene and blood pressure [ 65 ].
Moreover, while the mechanisms involved in regulation of renin in the collecting
duct are not elucidated yet [ 66 ], it appears that increase in renin synthesis and
activity independent of blood pressure at this location may contribute to the
7 Pathophysiological Insights in Resistant Hypertension