Signal Transduction of Mineralocorticoid and Angiotensin II Receptors in the Central Control of Sodium Appetite: A Narrative Review

Sodium appetite is an innate behavior occurring in response to sodium depletion that induces homeostatic responses such as the secretion of the mineralocorticoid hormone aldosterone from the zona glomerulosa of the adrenal cortex and the stimulation of the peptide hormone angiotensin II (ANG II). The synergistic action of these hormones signals to the brain the sodium appetite that represents the increased palatability for salt intake. This narrative review summarizes the main data dealing with the role of mineralocorticoid and ANG II receptors in the central control of sodium appetite. Appropriate keywords and MeSH terms were identified and searched in PubMed. References to original articles and reviews were examined, selected, and discussed. Several brain areas control sodium appetite, including the nucleus of the solitary tract, which contains aldosterone-sensitive HSD2 neurons, and the organum vasculosum lamina terminalis (OVLT) that contains ANG II-sensitive neurons. Furthermore, sodium appetite is under the control of signaling proteins such as mitogen-activated protein kinase (MAPK) and inositol 1,4,5-thriphosphate (IP3). ANG II stimulates salt intake via MAPK, while combined ANG II and aldosterone action induce sodium intake via the IP3 signaling pathway. Finally, aldosterone and ANG II stimulate OVLT neurons and suppress oxytocin secretion inhibiting the neuronal activity of the paraventricular nucleus, thus disinhibiting the OVLT activity to aldosterone and ANG II stimulation.

Computational mechanisms of osmoregulation: a reinforcement learning model for sodium appetite

Homeostatic control with oral nutrient intake is a vital complex system involving the orderly interactions between the external and internal senses, behavioral control, and reward learning. Sodium appetite is a representative system and has been intensively investigated in animal models of homeostatic systems and oral nutrient intake. However, the system-level mechanisms for regulating sodium intake behavior and homeostatic control remain unclear. In the current study, we attempted to provide a mechanistic understanding of sodium appetite behavior by using a computational model, the homeostatic reinforcement learning model, in which homeostatic behaviors are interpreted as reinforcement learning processes. Through simulation experiments, we confirmed that our homeostatic reinforcement learning model successfully reproduced homeostatic behaviors by regulating sodium appetite. These behaviors include the approach and avoidance behaviors to sodium according to the internal states of individuals. In addition, based on the assumption that the sense of taste is a predictor of changes in the internal state, the homeostatic reinforcement learning model successfully reproduced the previous paradoxical observations of the intragastric infusion test, which cannot be explained by the classical drive reduction theory. Moreover, we extended the homeostatic reinforcement learning model to multi-modal data, and successfully reproduced the behavioral tests in which water and sodium appetite were mediated by each other. Finally, through an experimental simulation of chemical manipulation in a specific neural population in the brain stem, we proposed a testable hypothesis for the function of neural circuits involving sodium appetite behavior. The study results support the idea that osmoregulation via sodium appetitive behavior can be understood as a reinforcement learning process and provide a mechanistic explanation for the underlying neural mechanisms of sodium appetite and homeostatic behavior.

Participation of calcium channels in the action of angiotensin II in astrocytes

Background: The renin-angiotensin-aldosterone system is the main regulator of blood pressure and blood volume, with most effects being mediated by angiotensin II (Ang-II) - responsible, in the central nervous system, for actions such as thirst and sodium appetite. Astrocytes are believed to mediate such a response, as they express receptors for Ang-II and respond directly to dehydration with impacting morphological changes in the synaptic microenvironment. Many of its functions involve L-type calcium channels (LTCCs). Objectives: Evaluate the participation of LTCCs in the effects induced by AngII in cultured hypothalamic astrocytes. Methods: The effect of incubation with verapamil on the morphological responses induced by Ang-II was evaluated in hypothalamic astrocyte culture, by analyzing the expression of the cytoskeletal protein GFAP and the cell viability by the MTT assay, by immunofluorescence. Results: Incubation with Ang-II reduced the cell area considerably due to GFAP expression in relation to the control group (DMEM p<0.001), indicating that the results observed on GFAP expression did not result from cell death. Conclusion: Incubation with Ang-II alters the astrocyte morphology, reducing its area, effect at least in part, blocked by the action of Verapamil, indicating the participation of LTCCs in the mediation of this process.

Sodium Imbalance in Mice Results Primarily in Compensatory Gene Regulatory Responses in Kidney and Colon, but Not in Taste Tissue

Renal excretion and sodium appetite provide the basis for sodium homeostasis. In both the kidney and tongue, the epithelial sodium channel (ENaC) is involved in sodium uptake and sensing. The diuretic drug amiloride is known to block ENaC, producing a mild natriuresis. However, amiloride is further reported to induce salt appetite in rodents after prolonged exposure as well as bitter taste impressions in humans. To examine how dietary sodium content and amiloride impact on sodium appetite, mice were subjected to dietary salt and amiloride intervention and subsequently analyzed for ENaC expression and taste reactivity. We observed substantial changes of ENaC expression in the colon and kidney confirming the role of these tissues for sodium homeostasis, whereas effects on lingual ENaC expression and taste preferences were negligible. In comparison, prolonged exposure to amiloride-containing drinking water affected β- and αENaC expression in fungiform and posterior taste papillae, respectively, next to changes in salt taste. However, amiloride did not only change salt taste sensation but also perception of sucrose, glutamate, and citric acid, which might be explained by the fact that amiloride itself activates bitter taste receptors in mice. Accordingly, exposure to amiloride generally affects taste impression and should be evaluated with care.