title: Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, 36, Sanhao Street, Shenyang, 110004, China. daishy2014@163.com.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Dai
authors.affiliation: Department of Physiology and Pathophysiology, Life Science Research Center, Hebei North University, Zhangjiakou City, Hebei, China. sun003@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Physiology and Pathophysiology, Life Science Research Center, Hebei North University, Zhangjiakou City, Hebei, China. zhangeping@sina.com.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Life Science Research Center, Hebei North University, Zhangjiakou City, Hebei, China. djl999shengli@163.com.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, 36, Sanhao Street, Shenyang, 110004, China. daishy2014@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, 36, Sanhao Street, Shenyang, 110004, China. daishy2014@163.com.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Sun
mesh_terms: D000704:Analysis of Variance; D057912:Angiotensin II Type 2 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D064791:Desoxycorticosterone Acetate / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D011725:Pyridines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D012965:Sodium Chloride / Q000633:toxicity*; D013686:Telemetry
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D016207:Cytokines; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; C073402:PD 123319; D012965:Sodium Chloride; D064791:Desoxycorticosterone Acetate