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CD86 expressed by dendritic cells, as well as IL-15, a cytokine synthesized by renal
epithelium as a result of inflammation [ 165 ].
The subsequent migration of activated T cells and macrophages in the kidney
and blood vessels contributes to the renal and vascular impairment through synthe-
sis of inflammatory cytokines (IL-6, interferon-γ, and IL-17) [ 162 ]. At the vascular
level, the inflammatory cytokines synthesized by activated T cells lead to increased
arterial stiffness, as studies report detectable levels of IL-1β in patients with resis-
tant hypertension, while apparently TNF-α is likely to intervene in the mediation of
vascular damage as well [ 166 , 167 ]. Other inflammatory biomarkers involved in the
vascular dysfunction associated with resistant hypertension are E-selectin,
P-selectin, and MCP1, high levels there of being recorded in the serum of patients
with hypertension [ 168 ].
Therapeutic correlation Due to the involvement of memory T cells in cytokine
synthesis, which leads to angiotensinogen production and Na+ retention, prevention
of end-organ damage and hypertension could be achieved through interventions
which would target the formation or accumulation of specific subsets of memory T
cells in the kidney [ 169 ]. On the other hand, there are also recent discussions about
the design of a vaccine for hypertension [ 170 ] which would target the specific pep-
tides involved in the pathogenic mechanism. Furthermore, given that isoketal scav-
engers prevent the development of the immune cascade associated with hypertension,
these modified proteins represent a potential target for new treatment strategy in
resistant hypertension [ 164 ].
In addition to the dynamics of the cellular processes involved in the immune
aspect of RH, studies also assign an important contribution to oxidative stress in the
increase of hypertension, although the etiopathogenic signification has not been
proven yet in humans. Nevertheless, it has been ascertained that RH patients display
higher oxidative stress levels, reflected in the endothelial dysfunction and cardio-
vascular modifications specific for hypertension [ 171 ].
Oxidative stress (involving reactive oxygen species – ROS) is generated by the
family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family
(Nox1, Nox2, Nox4, and Nox5), mitochondrial enzymes, xanthine oxidase, and
uncoupled NO synthase (NOS), through a complex molecular mechanism which
results from the interaction between the increased expression of adhesion mole-
cules, synthesis of proinflammatory and pro-thrombotic factors, and increased
endothelin-1 secretion [ 172 ]. Consequently, in the dynamics of the molecular
processes, increased levels of oxidative stress also lead to decrease of nitric oxide
levels [ 15 , 173 ], with the involvement of COX-2 enzyme of the cyclooxygenase
family, whose increased levels were recorded in essential hypertensive patients, and
also to the impaired antioxidant ability of the cardiovascular, renal, and nervous
systems [ 174 ].
There is also a subtle interaction between these processes at the level of the cen-
tral nervous system, as research has shown that the genetic manipulation of oxida-
tive stress in the subfornical organ on the dorsal part of the third ventricle influences
hypertension as well as T lymphocyte activation [ 162 ]. As we have already dis-
A. Burlacu and A. Covic