Effects of targeted disruption of the mouse angiotensin II type 2 receptor gene on stress‐induced hyperthermia

Abstract

; Aguilera et al. 1995). AT1 mediates all the well-known central actions of AII, including those involved in blood pressure regulation. By contrast, the physiological roles played by the AT2 receptor in the brain are as yet poorly defined. Recently, two laboratories developed mice deficient in AT2. These mice showed (i) increased pressor responses to AII and a lower resting body temperature (Hein et al. 1995;Ichiki et al. 1995) and (ii) attenuated exploratory behaviour and a reduction in spontaneous movements. These findings suggest that endogenous AII regulates central nervous functions via AT2. Animals exposed to stressors usually show activation of the sympathetic nervous system and the hypothalamopituitary adrenocortical axis, with consequent increases in body temperature, blood pressure, heart rate and the plasma concentration of adrenocorticotrophic hormone (McCubbin et al. 1991;Stanford & Samon, 1993). Recently, brain AII and its receptors have been shown to contribute to some stress-induced responses in rats. For example, we found that central administration of an AT2 antagonist, but not of an AT1 antagonist, attenuated the interleukin-1 (IL_1)-induced hyperthermic response . This suggests that AT2 in the brain may modulate (or mediate) the hyperthermia induced by immunological stress. On the other hand, to demonstrate inhibition of the hyperthermic, pressor and tachycardic responses to restraint stress required central injection of an AT1 antagonist (Saikiet al. 1997). Inhibition by an AT1 antagonist of the pressor response to heat or footshock stress has also been reported (Cierco & Israel, 1994;Kregel et al. 1994). Taken together, these findings suggest that brain AII and its receptors (AT1 and AT2) may play important roles in physiological reactions (such as body temperature increases) to several stress protocols in rats and they indicate the separate involvement of AT1 and AT2 in the effects induced by particular forms of stress. 1. We have previously reported that brain angiotensin II type 2 receptors (AT2) contribute to immunological stress-induced hyperthermia (fever) in rats. Now, in mice, we report the effect of AT2 gene disruption on the hyperthermia induced by immunological (interleukin-1 (IL_1) injection) and non-immunological (saline injection or cage switch) stress. 2. AT2-deficient and control mice both showed typical circadian rhythmicity in body temperature and physical activity. During the latter half of the dark period, AT2-deficient mice exhibited a lower body temperature than the controls. 3. By comparison with the controls, AT2-deficient mice exhibited: (i) a significantly smaller hyperthermia after intraperitoneal (i.p.) injection of IL-1â; (ii) significantly greater increases in body temperature and physical activity after i.p. saline; and (iii) a significantly greater hyperthermia (but a similar increase in activity) during cage-switch stress. 4. These results suggest that AT2, presumably in the brain, plays important roles in stressinduced hyperthermia in mice. 9055Keywords:

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…Induces a profound reduction in both subcutaneous and visceral adiposity (Grobe et al, 2010). Leads to enhanced brown adipose tissue thermogenesis and white adipose tissue lipolysis, possibly through AT2 receptor (Watanabe et al, 1999;de Kloet et al, 2011).…”

Angiotensin II AT1receptor blockade selectively enhances brain AT2receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats

“…In the rat, there are high numbers of AT 2 receptors in the locus coeruleus (Tsutsumi and Saavedra 1991a), the major site for catecholamine synthesis projecting to the forebrain (Sawchenko and Swanson 1981). A role for brain AT 2 receptors in the regulation of central catecholamine formation and stress is further supported by the decrease in AT 2 receptor mRNA in the locus coeruleus and inferior olive of rats submitted to chronic cold stress (Peng and Phillips 2001) and by the increased stress response (Watanabe et al 1999), HPA axis stimulation and AT 1 receptor expression in AT 2 gene-disrupted (AT 2 -/-) mice.…”

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

“…Thus, it appears that AT 2 gene-deleted mice present a constitutively stimulated hypothalamic-pituitary-adrenal axis. These results may explain the phenotype in this model, not only that of enhanced stimulation to exogenously administered Ang II [12, 13], but also their increased response to stress, such as the greater increase in physical activity after an injection of saline and their greater evoked hyperthermia after saline injection and after cage-switch stress [14]. Mice used in this study were analyzed only 1 day after air transportation and arrival at NIH.…”

“…The targeted disruption of the mouse AT 2 gene significantly increased blood pressure and the sensitivity to the pressor action of exogenous Ang II, indicating the possibility of enhanced AT 1 receptor stimulation [12, 13]. In addition, AT 2 gene-disrupted mice manifest behavioral alterations including anxiety-like behavior, and increased sensitivity to stress [12, 13, 14, 15]. …”