Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats

Background: recent studies demonstrate that there are sex differences in the expression of angiotensin receptor type 2 (at2-r) in the kidney and that at2-r plays an enhanced role in regulating blood pressure (bp) in females. also,brain at2-r activation has been reported to negatively modulate bp and sympathetic outflow. the present study investigated whether the central blockade of endogenous at2-r augments deoxycorticosterone acetate (doca)/salt-induced hypertension in both male and female rats. methods: all rats were subcutaneously infused with doca combined with 1% nacl solution as the sole drinking fluid. bp and heart rate (hr) were recorded by telemetric transmitters. to determine the effect of central at2-r on doca/salt-induced hypertension,male and female rats were intracerebroventricularly (icv) infused with at2-r antagonist,pd123,319,during doca/salt treatment. subsequently,the paraventricular nucleus (pvn) of the hypothalamus,a key cardiovascular regulatory region of the brain,was analyzed by quantitative real-time pcr and western blot. results: doca/salt treatment elicited a greater increase in bp in male rats than that in females. icv infusions of the at2-r antagonist significantly augmented doca/salt pressor effects in females. however,this same treatment had no enhanced effect on doca/salt-induced increase in the bp in males. real-time pcr and western blot analysis of the female brain revealed that doca/salt treatment enhanced the mrna and protein expression for both antihypertensive components including at2-r,angiotensin-converting enzyme (ace)-2,and interleukin (il)-10 and hypertensive components including angiotensin receptor type 1 (at1-r),ace-1,tumor necrosis factor (tnf)-α,and il-1β,but decreased mrna expression of renin in the pvn. the central blockade of at2-r reversed the changes in mrna and protein expressions of ace-2,il-10,and renin,further increased the expressions of tnf-α and il-1β,and kept higher the expressions of at1-r,ace-1,and at2-r. conclusions: these results indicate that endogenous at2-r activation in the brain plays an important protective role in the development of doca/salt-induced hypertension in females,but not in males. the protective effect of at2-r in females involves regulating the expression of brain renin-angiotensin system components and proinflammatory cytokines. © dai et al.