Key result
Aldosterone drives sodium intake via mineralocorticoid receptor signaling and ~6-fold Sv2c upregulation in mice.
Why the study?
Although aldosterone signals through the mineralocorticoid receptor to restrict sodium excretion and promote salt appetite during sodium deficiency, its role in regulating neuronal function was poorly understood.
Does mineralocorticoid receptor (MR) and SV2C signaling in HSD2 neurons mediate aldosterone-induced synaptic remodeling and sodium appetite in mice?
Does mineralocorticoid receptor (MR) and SV2C signaling in HSD2 neurons mediate aldosterone-induced synaptic remodeling and sodium appetite in mice?
This preclinical study demonstrates that aldosterone promotes salt appetite by acting directly on brainstem HSD2 neurons via mineralocorticoid receptors to drive a selective synaptic transcriptional program—most notably upregulating the synaptic vesicle protein SV2C—offering a molecular mechanism for excess dietary sodium intake in conditions like primary aldosteronism.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for salt appetite mechanisms in aldosteronism; leaves open human relevance of MR-Sv2c signaling in HSD2 neurons.
Sodium deficiency increases aldosterone, which signals through the mineralocorticoid receptor (MR) to restrict sodium excretion and promote salt appetite. Despite aldosterone's importance in maintaining hydromineral balance, its role in regulating neuronal function is poorly understood. Here, we define the transcriptional response to aldosterone in neurons and demonstrate that MR signaling in HSD2 neurons is essential for aldosterone-induced sodium appetite. Disruption of MR in HSD2 neurons impaired sodium appetite following deficiency and abolished saline intake in response to aldosterone. Single-nucleus RNA sequencing of the caudal nucleus of the solitary tract (NTS) revealed that aldosterone selectively regulates gene expression in HSD2 neurons, with enrichment for transcripts associated with synaptic function. Consistent with this, aldosterone increased the paired-pulse ratio at HSD2 neuron synapses, indicating reduced synaptic depression during repeated stimulation. Notably, Sv2c, encoding synaptic vesicle glycoprotein 2C, exhibited the greatest increase in expression after aldosterone treatment, and its disruption in HSD2 neurons reduced saline ingestion, identifying SV2C as a mediator of mineralocorticoid-induced sodium appetite. Together, these findings reveal a selective aldosterone-induced transcriptional program associated with enhanced synaptic transmission in HSD2 neurons and identify a molecular mechanism through which aldosterone promotes sodium appetite.
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McDonough et al. (2026) studied Aldosterone-induced sodium appetite and sodium deficiency. Aldosterone administration and CRISPR/Cas9-mediated disruption of Nr3c2 or Sv2c in HSD2 neurons vs. Vehicle administration or control CRISPR/Cas9 targeting Rosa26 (AAV-DIO-SaCas9-U6-sgRosa26) was evaluated on 0.5 M NaCl intake, HSD2 neuron transcriptional profiling (snRNA-seq), and synaptic paired-pulse ratio. Aldosterone signaling via mineralocorticoid receptors in HSD2 neurons altered 183 genes (~6-fold increase in Sv2c), whereas MR or Sv2c disruption abolished or reduced 0.5 M NaCl intake in mice.
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