Increased Angiotensin II AT₁ Receptor Expression in Paraventricular Nucleus and Hypothalamic-Pituitary-Adrenal Axis Stimulation in AT₂ Receptor Gene Disrupted Mice

Abstract

Angiotensin II AT₂ receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT₁ receptors. We studied hypothalamic AT₁ receptor binding and mRNA by receptor autoradiography and in situ hybridization, adrenal catecholamines by HPLC, adrenal tyrosine hydroxylase mRNA by in situ hybridization and pituitary and adrenal hormones by RIA in AT₂ receptor-gene disrupted mice and wild-type controls.To confirm the role of adrenal AT₁ receptors, we treated wild-type C57 BL/6J mice with the AT₁ antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT₂ receptor transcription, we found increased AT₁ receptor binding in brain areas involved in the regulation of the hypothalamic-pituitary-adrenal axis, the hypothalamic paraventricular nucleus and the median eminence, and increased adrenal catecholamine synthesis as shown by higher adrenomedullary tyrosine hydroxylase mRNA and higher adrenal dopamine, norepinephrine and epinephrine levels when compared to wild-type mice. In addition, in AT₂ receptor gene-disrupted mice there were higher plasma adrenocorticotropin (ACTH) and corticosterone levels and lower adrenal aldosterone content when compared to wild-type controls. Conversely, AT₁ receptor inhibition in CB57 BL/6J mice reduced adrenal tyrosine hydroxylase mRNA and catecholamine content and increased adrenal aldosterone content. These results can help to explain the enhanced response of AT₂ receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT₁ and AT₂ receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT₁ receptor expression, and suggest that expression of AT₁ receptors can be dependent on AT₂ receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model.

Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia

“…In addition, it is apparent that there is a reciprocal regulation between receptor subtypes (46,49), and the direction of the regulation depends on both the cell type and the hormonal milieu to which it is exposed. In several tissues, there is cross talk between AT1 and AT2 receptors, and the expression of AT1 receptors can be dependent on AT2 receptor expression (3,46). Furthermore, a direct, positive effect of estrogens on the density of AT2 receptors has been demonstrated in the human myometrium (33).…”

“…Interestingly, it has been shown that estrogen modifies AT2 expression in the myometrium (33). Moreover, both receptors can mutually influence their gene expression profiles (3). Therefore, in view of the observed estrogen-induced downregulation of AT1 receptors in anterior pituitary, we set out to determine whether in vivo estrogen treatment modified the expression and function of AT2 receptors in this tissue.…”

Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT1 Receptor Antagonists in the Brain

“…This report is based on the finding of enhanced neurological deficits in AT 2 receptor knockout mice following middle cerebral artery occlusion. The authors did not consider that failure of AT 2 receptor transmission results in enhanced brain AT 1 receptor expression (Armando et al, 2002), a finding which can explain the increased sensitivity of AT 2 receptor knockout mice to ischemia. In addition, blockade of Ang II synthesis with ACE inhibitors should result in a decrease in both AT 1 and AT 2 receptor stimulation.…”

AT 1 Receptor Blockade Regulates the Local Angiotensin II System in Cerebral Microvessels From Spontaneously Hypertensive Rats

“…The feedback between AT 1 /AT 2 receptors have been confirmed in AT 2 receptor knockout mice, where absence of AT 2 receptors correlates with increased AT 1 receptor binding and mRNA in hypothalamus, adrenal gland and kidney. [27][28][29] The hypothesis of AT 1 /AT 2 receptor cross-talk including activation of phosphatases by AT 2 receptor stimulation suppressing mitogen-activated protein kinase activation and counteracting AT 1 receptor effects 30 assumed same cell localization of both receptors. However, we have found that in cerebral microvessels, whereas AT 1 receptors colocalize with endothelial markers indicating an endothelial localization, AT 2 receptors do not.…”