109associated protein, adducin, in enhancing the Na-K function and increasing sodium
reabsorption and blood pressure.
Among the mechanisms involved in RH pathogeny, experimental studies have
described the involvement of the α2-Na+ pump, whose pathologic upregulation
leads to excessive Ca(2+) entry and signaling, contributing significantly to blood
pressure elevation [ 157 ]. Moreover, several trials have attributed the molecular
identity of the H(+) transport pathway to the voltage-gated proton channel, HV1,
which promotes superoxide production in medullary thick ascending limb nephron
segments in the presence of decreased levels of intracellular sodium, thus contribut-
ing to the development of hypertension and renal disease [ 158 ].
Oxidative Damage and Inflammation
In recent years, there has been increasing evidence related to the involvement of the
immune system in the pathogenic mechanism of hypertension. A neuroimmune axis
[ 159 ] has been proposed which connects the sympathetic nervous system, immune
cells, the production of cytokines, and vascular and renal dysfunction, orchestrated
in a complex interaction that brings about severe and resistant hypertension. As our
discussion on the implication of the immune system will unfold, we will attempt to
present the latest data that seem to substantiate the theory that one of the multiple
facets of RH could be that of autoimmune disease [ 160 ].
Thus, studies have reported the accumulation of macrophages and long-lived
memory T cells [ 161 ] in the kidneys and blood vessels of humans and experimental
animals with RH, and the impaired blood pressure response of lymphocyte- deficient
mice to several stimuli (such as angiotensin II, increased salt levels, and norepi-
nephrine) can be restored by the adoptive transfer of T cells. Immune cell activation
in hypertension is apparently regulated via the central nervous system, since experi-
mental data has shown that damage to the anteroventral third ventricle impedes
T-cell activation triggered by angiotensin II.
It is therefore likely that the initial increase in blood pressure termed as “prehy-
pertension” [ 162 ], caused by over-activation of the sympathetic pathway in response
to common mild hypertensive stimuli, generates neoantigens by modifications in
protein structure caused by oxidative stress [ 163 ]. It is reported that proteins modi-
fied through oxidation by highly reactive γ-ketoaldehydes (isoketals) are synthesized
by dendritic cells due to hypertensive stimuli administrated to animal models [ 164 ].
Accumulation of isoketals leads to the activation of the antigen-presenting function
of these cells and represents the source of self-antigens. The immune cascade is
consequently initiated, the dendritic cell playing an essential role through its func-
tion in processing and presenting the neoantigens and neopeptides resulted.
Activation of dendritic cells results in increased production of IFN-γ and IL-17A
and increased proliferation of T cells, mainly CD8+. Furthermore, experimental
studies show that an important contribution in the consequent activation of CD8+ T
lymphocytes may be played by the co-stimulatory molecules CD70, CD80, and
7 Pathophysiological Insights in Resistant Hypertension