102
Recent studies have shown the involvement of kidney local angiotensin II pro-
duction in regulation of blood pressure and proximal tubular reabsorption [ 93 ] on
rats and mice [ 94 ]. Moreover, as internalization of angiotensin II has been demon-
strated, it is still uncertain if this process is involved in intracrine and signaling
pathways [ 95 ].
Similarly, the RAAS in the hematopoietic bone marrow is involved in mediation
of pathobiological dysregulations of hematopoiesis, while the presence of ACE has
been ascertained in human primitive lymphohematopoietic cells, as well as in
embryonic, fetal, and adult hematopoietic tissues [ 96 ]. It appears that angiotensin II
triggers the proliferation and differentiation of CD34+ stem cells through binding
with angiotensin II type 1a membrane receptors. Moreover, the human umbilical
cord blood seems to comprise a local RAAS, and expression of renin, angiotensino-
gen, and ACE mRNAs has been demonstrated, with possible involvement in cellular
growth in several tissues [ 97 ].
Existence of local RAAS in the brain has been demonstrated in dendritic pro-
cesses of neurons in the medial nucleus tractus solitarii and area postrema [ 98 ],
areas involved in central cardiovascular effects triggered by angiotensin II, through
identification of intracellular and plasmalemmal AT1 receptors and of intraneuronal
production of angiotensin II [ 99 ].
In the pancreas, the local RAAS has been identified in pancreatic acinar, isled,
duct, endothelial, and stellate cells, while its expression is modulated in accordance
with various stimuli such as hypoxia, pancreatitis, islet transplantation, hyperglyce-
mia, and diabetes mellitus [ 100 ].
The presence of local intracrine RAAS has been ascertained in the liver as well,
where it has been reported to act in concert with or independently of the endocrine
renin system [ 101 ].
Tissue Kallikrein-Kinin
Within the framework of these new concepts introduced in the description of RAAS,
it seems that hypertension could be in fact the consequence of an imbalance between
the vasodepressor and vasopressor hormonal systems. Moreover, local hormonal
systems could be put together by vasodepressor hormones such as kinins, prosta-
glandins, and endothelium-derived relaxing factor. The tissue kallikrein-kinin sys-
tem could be involved in local regulation of circulation, renal function, as well as in
the acute antihypertensive effect of ACE-I [ 102 ].
Involved in several intracellular signaling pathways, angiotensin II contributes
significantly to the organ damage associated with RH. While the upregulation of its
intracellular signaling increases the risk for kidney damage in hypertension [ 103 ],
its inhibitory influence on several receptors and regulatory proteins in the insulin
signaling pathways leads to a higher insulin sensitivity, thus decreasing the risk for
type 2 diabetes mellitus [ 104 ]. The pathological changes in the heart and blood ves-
sels generated by the abnormal activity of fibroblasts involve multiple intracellular
A. Burlacu and A. Covic