95and are associated with PPAR-α (fibrates) or gene therapy, which upregulate
20-HETE synthesis. Another outcome of this therapy could possibly be obtained in
hindering the progression of glomerular fibrosis and renal fibrosis [ 27 ].
New Theories
Gαi2-Protein-Gated Pathways
A new hypothesis introduced in the attempt to decipher the complex framework of
salt-resistant hypertension advances the involvement of paraventricular nucleus
Gαi2-protein-gated signal transduction pathways in the sympathetically mediated
process of renal sodium retention. Experimental investigations on naive Brown
Norway, Dahl salt-resistant, and scrambled oligodeoxynucleotide-infused Dahl
salt-resistant but not DSS rats have demonstrated that this central molecular path-
way plays an important role in the mediation of sympathoinhibitory renal nerve-
dependent responses triggered in the mechanism of sodium homeostasis and of a
salt-resistant phenotype [ 29 ].
Microglia
Currently, the possibility to take into account microglia as a new target for treatment
of RH is being investigated, as the activation of these cells in autonomic brain
regions is characteristic for the neuroinflammation in neurogenic hypertension [ 30 ].
Apparently, the microglia are the main cellular factors in the mediation of neuroin-
flammation and the modulation of neuronal excitation, mechanisms involved in
elevated blood pressure. The hallmarks of microglial activation are microgliosis
and proinflammatory cytokine upregulation. Moreover, research has ascertained
that angiotensin II-induced hypertension is correlated with activation of microglia
and increases in proinflammatory cytokines [ 31 ] in the paraventricular nucleus.
Therapeutic correlation Studies performed on rats have proved that the targeted
depletion of microglia has decreased neuroinflammation, glutamate receptor expres-
sion in the paraventricular nucleus, plasma vasopressin level, kidney norepineph-
rine concentration, and blood pressure [ 32 ]. Moreover, the transfer of preactivated
cells into the brains of normotensive mice determined a considerably prolonged
pressor response to intracerebroventricular injection of angiotensin II, while the
inactivation of microglia leads to the disappearance of these effects [ 33 ].
Bone Marrow
Bone marrow contribution to the mechanisms of hypertension resides in the increase
of peripheral inflammatory cells and their extravasation into the brain (BM – brain
interaction) [ 30 ]. Moreover, the hypothesis advancing the involvement of
7 Pathophysiological Insights in Resistant Hypertension