Regulation of angiotensin II receptors beyond the classical pathway

The RAS (renin–angiotensin system) plays a role not only in the cardiovascular system, including blood pressure regulation, but also in the central nervous system. AngII (angiotensin II) binds two major receptors: the AT₁ receptor (AngII type 1 receptor) and AT₂ receptor (AngII type 2 receptor). It has been recognized that AT₂ receptor activation not only opposes AT₁ receptor actions, but also has unique effects beyond inhibitory cross-talk with AT₁ receptor signalling. Novel pathways beyond the classical actions of RAS, the ACE (angiotensin-converting enzyme)/AngII/AT₁ receptor axis, have been highlighted: the ACE2/Ang-(1–7) [angiotensin-(1–7)]/Mas receptor axis as a new opposing axis against the ACE/AngII/AT₁ receptor axis, novel AngII-receptor-interacting proteins and various AngII-receptor-activation mechanisms including dimer formation. ATRAP (AT₁-receptor-associated protein) and ATIP (AT₂-receptor-interacting protein) are well-characterized AngII-receptor-associated proteins. These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states. Moreover, the possible cross-talk between PPAR (peroxisome-proliferator-activated receptor)-γ and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of RAS in the metabolic syndrome, and interestingly some ARBs (AT₁-receptor blockers) have been reported to have an AT₁-receptor-blocking action with a partial PPAR-γ agonistic effect. These emerging concepts concerning the regulation of AngII receptors are discussed in the present review.