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

Abstract

Recent evidence shows that reexpression and upregulation of angiotensin II (ANG II) type 2 (AT2) receptor in adult tissues occur during pathological conditions such as tissue hyperplasia, inflammation, and remodeling. In particular, expression of functional AT2 receptors in the pituitary and their physiological significance and regulation have not been described. In this study, we demonstrate that chronic in vivo estrogen treatment, which induces pituitary hyperplasia, enhances local AT2 expression (measured by Western blot and RT-PCR) concomitantly with downregulation of ANG II type 1 (AT1) receptors. In vivo progesterone treatment of estrogen-induced pituitary hyperplasia did not modify either the ANG II receptor subtype expression pattern or octapeptide-induced and AT1-mediated calcium signaling. Nevertheless, an unexpected potentiation of the ANG II prolactin-releasing effect was observed in this group, and this response was sensitive to both AT1 and AT2 receptor antagonists. These data are the first to document that ANG II can act at the pituitary level through the AT2 receptor subtype and that estrogens display a differential regulation of AT1 and AT2 receptors at this level.prolactin; calcium signaling; Western blot; reverse transcriptasepolymerase chain reaction ANGIOTENSIN II (ANG II) is a key regulator of cardiovascular homeostasis and is also involved in various biological functions, such as hormone secretion, tissue growth, and neuronal activation. Two ANG II receptor subtypes, AT1 and AT2, first distinguished on a pharmacological basis, have been identified by expression cloning from various species, and most biological functions exerted by ANG II are mediated by the AT1 receptor subtype. The AT2 receptor subtype is abundantly and widely distributed in fetal tissues, although its expression is dramatically decreased after birth, being restricted to a few organs such as brain, adrenal, heart, myometrium, and ovary (25,36). Nevertheless, the AT2 receptor is reexpressed in the adult animal under certain pathological conditions, such as ovarian atresia, cardiac and vascular injury, nerve crush, wound healing, and kidney obstruction. AT2 receptors may act as modulators of complex biological programs involved in embryonic development, cell differentiation, tissue protection, and regeneration, as well as in programmed cell death (25, 36).It has been described that all of the components of the reninangiotensin system (RAS) are present in the pituitary and that ANG II is produced locally (13). The anterior pituitary predominantly expresses the AT1B isoform of the AT1 receptor (31, 41), with a low expression of the AT1A isoform and the AT2 receptor subtype (41, 45). ANG II releases prolactin both in vivo and in vitro (14) and activates extracellular signal-related kinase 1/2 through a calcium-dependent, AT1 receptor-specific mechanism (47). Yet, participation of AT2 receptors in ANG II effects on pituitary function has not been described to date.Estrogens can modulate many aspects of the peripheral and pituit...

Estrogen Reduces Aldosterone, Upregulates Adrenal Angiotensin II AT₂ Receptors and Normalizes Adrenomedullary Fra-2 in Ovariectomized Rats

“…Progesterone effects on adrenal AT 2 receptors have not been studied. However, in the pituitary gland, progesterone does not alter the AT 2 receptor expression induced after estrogen-induced hyperplasia [40]. AT 2 receptor upregulation may also be a response to the high estrogen levels during our experiments, above those occurring during the estrous cycle but similar to those found during pregnancy.…”

Adenohypophyseal and hypothalamic GABA B receptor subunits are downregulated by estradiol in adult female rats

“…Intracellular Ca 2+ was performed as previously described using Fura-2/AM (tetracetoxymethylesther-Fura 2) as a fluorescent indicator Suarez et al, 2004). Briefly, adenohypophyseal cells were incubated for 30 min in a buffered saline solution (BSS: 140 mM NaCl, 3.9 mM KCl, 0.7 mM KH 2 PO 4 , 0.5 mM Na 2 HPO 4 ·12H 2 O, 1 mM CaCl 2 , 0.5 mM MgCl 2 , 20 mM Hepes, pH 7.5) in the presence of FURA-2/ AM 1.5 μM, 10 mM glucose, 0.1% BSA.…”

“…Furthermore estrogen treatment produces involution of somatotrophs and gonadotropin-producing cells (De Nicola et al, 1978). In addition, it has been shown that estrogens alter the sensitivity of adenohypophyseal cells to stimulatory and inhibitory factors, such as dopamine, TRH, angiotensin II and GABA (Apud et al, 1985;Diaz-Torga et al, 1998;Livingstone et al, 1998;Suarez et al, 2003Suarez et al, , 2004. Moreover, ovarian steroid hormones modulate GABAergic neurotransmission in various brain areas by altering GABA A R function or subunit composition (Herbison and Fenelon, 1995;Schumacher et al, 1989;Weiland and Orchinik, 1995).…”

The Involvement of Angiotensin Type 1 and Type 2 Receptors in Estrogen-Induced Cell Proliferation and Vascular Endothelial Growth Factor Expression in the Rat Anterior Pituitary

“…Additionally, the release of ang II from hypothalamus has been described to rise in response to estrogen [24]. Next, a chronic exposition to DES led to the upregulation of the AT2 receptor gene transcription and increase in the functional AT2 receptor expression in anterior pituitary of rats [25]. …”