Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT₁) receptors

Abstract

(AT 1A) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT 1A] with brain-restricted overexpression of AT1A receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT 1A compared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT 1A. Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in NSE-AT 1A mice compared with wild types. Fos immunohistochemistry, used to assess neuronal activation, demonstrated sodium depletion-enhanced activity in the anteroventral third ventricle region of the brain in NSE-AT 1A mice compared with control animals. The results show that brain-selective overexpression of AT 1A receptors results in enhanced salt appetite and altered water intake. This model provides a new tool for studying the mechanisms of brain AT 1A -dependent water and salt consumption. thirst; sodium appetite; transgenic mice; circumventricular organs; volume homeostasis; anteroventral third ventricle THERE IS SUBSTANTIAL EVIDENCE that activation of the reninangiotensin system (RAS) is involved in water and sodium intake. Thirst and sodium depletion are monitored by osmoreceptors and/or sodium receptors located at the periphery and in the brain (5). Although several candidates have been identified (6,27,28,49), the nature and mechanism of action of these receptors remain unclear. However, it is well known that systemically and brain-generated angiotensin II (ANG II) can act directly or indirectly on ANG II receptor type 1 (AT 1 ) receptors located in the lamina terminalis to produce water and salt intake (20,36). While the role and independence of centrally vs. peripherally generated ANG II in these responses still remain unclear, the pivotal involvement of central AT 1 receptors was established by studies where intracerebroventricular (ICV) administration of RAS antagonists reduced sodium appetite of sodium-depleted intact rats (41) and adrenalectomized rats (42). Furthermore, the exaggerated salt appetite observed in spontaneously hypertensive rats was reduced by central treatment with angiotensin-converting enzyme inhibitors, suggesting a role for the brain RAS in the exaggerated salt appetite in this model of hypertension (14).In rodents, water deprivation upregulates the AT 1 receptor in various areas of the brain, including the subfornical organ (SFO) and the anterior pituitary (43), as well as in the periphery (19). In addition, water and sodium intake can be abolished by pretreatment with selective antagonists ...

Granulocyte Colony Stimulating Factor Prevents Kidney Infarction and Attenuates Renovascular Hypertension

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Neuroendocrine characterization and anorexigenic effects of telmisartan in diet- and glitazone-induced weight gain

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Water deprivation-partial rehydration induces sensitization of sodium appetite and alteration of hypothalamic transcripts

“…Sodium appetite has been associated with hypothalamic genes linked to addiction (21). The elevated levels we found for Agt gene is also consistent with the increased sodium intake of animals with hyperactive brain RAS, inherited, such as in SHR, or genetically engineered, such as in transgenic mice overexpressing neuronal Agt or angiotensin AT 1 receptor genes (18,27). The effect on Agt is also in line with ANG II sensitizing the brain to become more responsive to the pressor effect of ANG II itself and sodium depletion (17,42).…”