Role of the central renin-angiotensin system in hypertension (Review)

Present in more than one billion adults, hypertension is the most significant modifiable risk factor for mortality resulting from cardiovascular disease. Although its pathogenesis is not yet fully understood, the disruption of the renin-angiotensin system (RAS), consisting of the systemic and brain RAS, has been recognized as one of the primary reasons for several types of hypertension. Therefore, acquiring sound knowledge of the basic science of RAS and the under- lying mechanisms of the signaling pathways associated with RAS may facilitate the discovery of novel therapeutic targets with which to promote the management of patients with cardiovascular and kidney disease. In total, 4 types of angiotensin II receptors have been identified (AT1R-AT4R), of which AT1R plays the most important role in vasoconstriction and has been most extensively studied. It has been found in several regions of the brain, and its distribution is highly associated with that of angiotensin-like immunoreactivity in nerve terminals. The effect of AT1R involves the activation of multiple media and signaling pathways, among which the most important signaling pathways are considered to be AT1R/JAK/STAT and Ras/Raf/MAPK pathways. In addition, the regulation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and cyclic AMP response element-binding (CREB) pathways is also closely related to the effect of ATR1. Their mechanisms of action are related to pro-inflammatory and sympathetic excitatory effects. Central AT1R is involved in almost all types of hypertension, including spontaneous hypertension, salt-sensitive hypertension, obesity-induced hypertension, renovascular hypertension, diabetic hypertension, L-NAME-induced hypertension, stress-induced hypertension, angiotensin II-induced hyper- tension and aldosterone-induced hypertension. There are 2 types of central AT1R blockade, acute blockade and chronic blockade. The latter can be achieved by chemical blockade or genetic engineering. The present review article aimed to high- light the prevalence, functions, interactions and modulation means of central AT-1R in an effort to assist in the treatment of several pathological conditions. The identification of angiotensin-derived peptides and the development of AT-2R agonists may provide a wider perspective on RAS, as well as novel therapeutic strategies.