Differential Expression of AT ₁ Receptors in the Pituitary and Adrenal Gland of SHR and WKY

Abstract

Abstract-The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT 1A , AT 1B , and AT 2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT 1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT 1B receptor mRNA was detected in the pituitary and adrenal gland. AT 2 receptor mRNA was prominent only in the adrenal gland. A ngiotensin II (ANG), the main active peptide of the renin-angiotensin system, acts at 2 distinct receptor subtypes, namely type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The role of AT 1 receptors in the regulation of cardiovascular functions, fluid homeostasis, and hormone release is well established, and several AT 1 receptor antagonists are used for the treatment of hypertension. 1 In rodents, 2 pharmacologically similar AT 1 receptor isoforms, AT 1A and AT 1B , exist, which are encoded by 2 distinct genes and are expressed and regulated differentially. 2-5 High levels of AT 1A receptor mRNA are present in the rodent brain, kidney, and vasculature, whereas AT 1B receptor mRNA is mainly expressed in the pituitary and adrenal glands. 6 -10 Although widely expressed in fetal and young rats, 11 in adult rats, the expression of AT 2 receptors is low and restricted to certain organs, such as the brain and adrenal gland. 1,12 The expression of all ANG receptor subtypes in the hypothalamo-pituitary-adrenal (HPA) axis, which is activated in response to stress, as well as the regulation of ANG receptors by restraint stress [13][14][15] implies important roles of the ANG system in the regulation of the activity of the HPA axis. Accordingly, ANG has been shown to regulate corticotropin-releasing factor, adrenocorticotropic hormone (ACTH), and corticosterone synthesis and secretion. 16 -18 Spontaneously hypertensive rats (SHR) show an impaired response and habituation to various forms of stress such as immobilization and exposure to heat or open field, and they differ in their neuroendocrine reaction to stress from normotensive Wistar-Kyoto rats (WKY). 19 -23 The ANG system has been implicated in the impaired stress response of SHR. 24 -27 There are several studies showing differences in the numbers of binding sites for radiolabeled ANG between SHR and WKY in the kidney, vasculature, heart, pituitary, adrenal gland, and brain, including the hypothalamus and neuronal cultures. 28 -32 Because AT 1A and AT 1B receptors are pharmacologically indistinguishable, the distinct expression of these AT 1 receptor isoforms was not addressed in these studies. Using a different approach, Iwai et al 33 could not detect differences of AT 1A mRNA levels in the brain and adrenal gland between WKY and SHR, whereas Raizada et a...

Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension

“…24 Because this receptor mediates the action of the peptide Ang II to stimulate adrenal aldosterone production, it is likely to contribute to the subsequent development of hypertension. Furthermore, it has been shown that blockade of Ang II production with ACE inhibitors, or interaction with the AT 1 receptor using a receptor antagonist will prevent development of hypertension in MLP offspring in contrast to nifedipene.…”

Albumin endocytosis in proximal tubule cells is modulated by angiotensin II through an AT 2 receptor-mediated protein kinase B activation

“…AT 2 receptors are expressed in the luminal membrane of the proximal tubule of adult animals (8,12) where albumin endocytosis occurs. We show that Ang II is operating to stimulate endocytosis via an AT 2 receptor.…”

“…Angiotensin receptors have seven transmembrane domains and belong to the family of G protein-coupled receptors (8,12). The AT 2 receptor shares 34% amino acid sequence homology with the AT 1 receptor.…”

“…The AT 2 receptor shares 34% amino acid sequence homology with the AT 1 receptor. The AT 2 receptor is expressed more abundantly during fetal development (8,12). However, studies in adults indicate that the AT 2 receptor could be up-regulated during specific conditions such as sodium depletion or glomerular injury (11,12).…”

“…The physiological role for AT 2 is not well known. It has been suggested that it plays an important role in the adult animal, probably by counteracting the physiological and pathophysiological effects mediated by the AT 1 receptor (8,11,12).…”