Mineralocorticoid-Induced Sodium Appetite and Renal Salt Retention: Evidence for Common Signaling and Effector Mechanisms

Abstract

An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum- and glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both the brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new therapeutic options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC.

Aldosterone-Sensing Neurons in the NTS Exhibit State-Dependent Pacemaker Activity and Drive Sodium Appetite via Synergy with Angiotensin II Signaling

“…Known target genes of theoretical interest, including the aldosterone-inducible subunits of the renal epithelial Na + channel, ENaC ( Scnn1a, Scnn1b and Scnn1g ), which also serves as the taste receptor for salt, were absent in control and deprived NTS HSD2 neurons (Figure S4A). Furthermore, consistent with the lack of a role for this otherwise attractive candidate (Fu and Vallon, 2014), the ENaC blocker amiloride did not inhibit firing of NTS HSD2 neurons from Na + -deprived mice (Figure S4C). On the other hand, NTS HSD2 neurons did express the aldosterone/MR target gene, serum/glucocorticoid regulated kinase 1 ( Sgk1 ), which in the kidney mediates aldosterone-induced trafficking of ion channels.…”

Gastrointestinal–Renal Axis: Role in the Regulation of Blood Pressure

“…[28][29][30][31][32][33] As aforementioned, the GI tract is the first organ exposed to ingested sodium. In the saltdepleted state, sensing the need for sodium in the tongue and stomach would lead the person to ingest more salt, 34 and in the addition, make the GI tract secrete hormones that increase absorption/reabsorption of sodium in different organs in the body, including the kidney. The converse occurs in the salt-replete state; less salt is ingested and the GI tract triggers the mechanisms to induce natriuresis and diuresis.…”

Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis

“…Fu et al [199] have assumed that aldosterone activates SGK1, Nedd4-2 and ENaC in both kidney and brain. They suggested that SGK1 and ENaC were involved in aldosterone-induced salt appetite, as ENaC also mediates the gustatory salt sensing.…”