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

Abstract

BackgroundRecent 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.MethodsAll 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.ResultsDOCA/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.ConclusionsThese 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.

Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor

“…The blood pressure lowering effect of AT2R stimulation was also attenuated by ovariectomy in female rats, which was most likely due to a decrease in AT2R expression in the PVN (and potentially other cardiovascular control areas) in ovariectomized rats [27]. Interestingly, Dai et al report that female rats have higher AT2R mRNA and protein expression in the PVN when compared with male rats; they further suggest that these higher AT2R levels elicit endogenous protection from the development of hypertension – in this study DOCA/NaCl-induced hypertension – only in females but not in males [32]. One consideration about this study is that the AT2R which were measured are likely associated with the peri-PVN AT2R neurons, as AT2R-containing neurons are not localized within the PVN [17].…”

Ultrastructural characterization of tumor necrosis factor alpha receptor type 1 distribution in the hypothalamic paraventricular nucleus of the mouse

“…Like glutamate, TNFα activity in the PVN is implicated in blood pressure control. Increased TNFα levels in the PVN, originating from a microglial source (Shi et al, 2010), are associated with the increased local neural activity (Kang et al, 2008, Yu et al, 2015), as well as elevated systemic blood pressure (Sriramula et al, 2013, Dai et al, 2015, Dange et al, 2015) and sympathetic activity (Dange et al, 2015, Yu et al, 2015) that accompany experimental hypertension (Shi et al, 2010, Yu et al, 2015). In addition, acute PVN TNFα administration increases sympathetic activity and blood pressure (Bardgett et al, 2014, Shi et al, 2014), and inhibiting central TNFα has been shown to block forms of experimental hypertension (Song et al, 2014) including the increase in blood pressure occurring with AngII administration (Sriramula et al, 2013).…”

“…Within the PVN, TNFα transcription is induced by challenges such as immunological stress (Kakizaki et al, 1999, Masson et al, 2015a). In addition, increased TNFα levels in the PVN are associated with increased local neural activity (Kang et al, 2008, Yu et al, 2015), as well as elevated systemic blood pressure (Sriramula et al, 2013, Dai et al, 2015, Dange et al, 2015) and sympathetic activity (Dange et al, 2015, Yu et al, 2015). All of these physiological responses accompany preclinical models of hypertension including the elevated blood pressure induced by angiotensin II (AngII), a critical blood pressure regulating molecule (Shi et al, 2010, Yu et al, 2015).…”

Protective Angiotensin Type 2 Receptors in the Brain and Hypertension

“…The cardiovascular actions of ICV-infused C21 appear more profound under disease conditions: it suppresses sympathetic outflow by improving baroreflex sensitivity in rats with heart failure [•40]; in SHR, it lowers blood pressure through sympathoinhibition, and improves spontaneous baroreflex sensitivity, via an NO-dependent mechanism [•41]; it lowers blood pressure in female DOCA-salt hypertensive rats via a mechanism that includes generation of the anti-inflammatory cytokine interleukin-10 [•42]. Furthermore, ICV infusions of the AT2R antagonist PD123,319 augmented the increase in blood pressure in female DOCA-salt hypertensive rats (no effect of PD123,319 was observed in male rats) [43]. These pharmacological studies using C21, CGP and PD123,319 are supported by data which demonstrate that chronic AAV2-mediated increased expression of AT2R in the NTS of 2 kidney-1 clip hypertensive rats decreases blood pressure and restores baroreflex sensitivity [•44].…”