Despite increasing aldosterone, elevated potassium is not necessary for activating aldosterone‐sensitive HSD2 neurons or sodium appetite

Abstract

Sodium appetite is a complex, motivated behavioral state. It requires low-sodium status detection and a coordinated drive to seek and ingest salty foods. Interestingly, this elaborate behavior can be elicited by administering a singular hormone, aldosterone (Formenti et al., 2013; Gasparini et al., 2018; Geerling & Loewy, 2008). Aldosterone is a mineralocorticoid produced in the zona glomerulosa of the adrenal cortex. It affects cells that express the mineralocorticoid receptor (MR) by translocating this receptor into the cell nucleus to promote genomic activity (Robertson et al., 1993). Aldosterone-sensitive cells also require the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), which protects the MR from glucocorticoids, leaving it more accessible to aldosterone (Funder et al., 1988; Naray-Fejes-Toth et al.,

HSD2 neurons are evolutionarily conserved and required for aldosterone-induced salt appetite

“…We also tested whether and to what extent peripheral aldosterone infusions increase the aldosterone concentration in CSF. As in rats (34), removing dietary sodium increased aldosterone production, with blood plasma concentrations reaching 113 to 414 ng/dL (Figure 5A). These sodium-deprived mice also had elevated aldosterone concentrations in CSF, ranging 19 to 47 ng/dL (Figure 5B).…”

“…Sodium deprivation activates HSD2 neurons and their chemogenetic stimulation increases saline intake. Switching rats to a low-sodium diet for one week is a simple and ethologically relevant way to boost aldosterone production, activate HSD2 neurons, and increase sodium appetite (34,54,60).…”

“…Peripheral infusion must have had a mixed effect, stimulating sodium appetite in the brain, while at the same time inhibiting sodium appetite as a consequence of peripheral hyperaldosteronism, which was not present in mice with i4V infusion. In either paradigm, consuming salt should briefly increase plasma sodium and blood volume, which would transiently reduce HSD2 neuron activity and sodium appetite (27,33,34,(99)(100)(101). Aldosterone-infused mice were not hypernatremic, but peripherally infused mice may have experienced some blood volume expansion due to the combination of (central) aldosterone-induced saline intake and (peripheral) aldosteroneinduced sodium retention.…”

“…These cells, known as the HSD2 neurons, are located in the nucleus of the solitary tract (NTS; 29,30), which is a hub for interoceptive information arriving from the heart, lungs, gut, and other viscera. Hypovolemic states like dietary sodium deprivation increase aldosterone production and activate the HSD2 neurons (27,(31)(32)(33)(34). HSD2 neurons from aldosterone-infused mice fire pacemaker-like action potentials (35), and chemogenetic stimulation of HSD2 neurons increases salt consumption (35,36).…”

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

“…DOCA-treated rats after access to hypertonic saline solutions (sodium chloride solution, 3%) drank significantly more water than vehicle-treated rats [ 98 ]. The presence of both the MR and the HSD2 on NTS neurons is essential because glucocorticoids may bind to MR, but HSD2 confers to aldosterone the specificity for the MR binding [ 99 ].…”