Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage

Background and aim: Angiotensin II acts through two major receptors: AT1-R and AT2-R. It is known that the stimulation of AT1-R mediates vasoconstriction, cell proliferation and fibrosis, aldosterone release and inflammatory response but, although the stimulation of AT2-R is thought to promote vasodilation and antiinflammatory effects, its real in-vivo functions are still unclear. The aim of this study was to investigate the effects of specific and selective AT2-R stimulation on the pathological events occurring in spontaneously hypertensive stroke-prone rats (SHRSPs). Methods and results: SHRSPs who were fed a high-salt diet underwent long-term treatment with vehicle or compound 21 (C21), a nonpeptide selective AT2-R agonist, at doses of 0.75, 5 and 10mg/kg per day. The vehicletreated rats developed brain abnormalities detectable by magnetic resonance imaging after 42.5W7.5 days, and died 43W9.5 days after the start of the dietary treatment. The highest C21 dose delayed the occurrence of brain damage (P <0.001 vs. vehicle-treated SHRSPs) and prolonged survival (P< 0.001)without affecting blood pressure. These beneficial effects of C21 were abolished by the administration of PD123319, an AT2-R antagonist. C21 treatment preserved renal structure by preventing inflammatory cell infiltration, collagen accumulation, and the neo-expression of vimentin; it also prevented the increased plasma renin activity and accumulation of urinary acute-phase proteins observed in the vehicletreated rats. Conclusion: Specific and selective AT2-R stimulation has beneficial effects on the pathological events occurring in SHRSPs. These data indicate a new avenue for the pharmacological treatment of diseases in which modulation of the renin–angiotensin system is required.