Aldosterone-mediated salt appetite driven by hindbrain HSD2 neurons

Miriam McDonough; Ahmet Kuralay; Trevor Butler; Silvia Gasparini; Joel Geerling; Jon Resch

doi:10.1152/physiol.2026.41.S1.2292151

Abstract only Aldosterone drives sodium appetite via its actions on neurons in the nucleus of the solitary tract (NTS) that express the glucocorticoid-inactivating enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD2). NTSHSD2 neurons are uniquely aldosterone-sensitive as they also express the mineralocorticoid receptor (MR) and are located near a circumventricular organ, allowing access to peripheral hormones. Moreover, activation of NTSHSD2 neurons drives sodium appetite, while their ablation reduces it. To investigate the molecular mechanisms driven by aldosterone signaling within NTSHSD2 neurons, we used CRISPR-Cas9 to induce indel mutations within Nr3c2, the gene encoding MR (MR KO), specifically in NTSHSD2 neurons. Our results show that MR KO significantly reduces NTSHSD2 neuron activity and sodium intake during sodium deficiency and completely abolishes sodium appetite induced by aldosterone. Given that MR regulates gene expression, we hypothesize that aldosterone-MR signaling induces sodium appetite by coordinating a transcriptional program promoting the excitability of NTSHSD2 neurons. To elucidate the transcriptional targets of MR within NTSHSD2 neurons that drive their increased activity, we performed single-nucleus RNA sequencing on NTSHSD2 neurons after 24 hours of aldosterone treatment. Importantly, transcriptional profiling of NTSHSD2 neurons identified nearly 200 differentially expressed genes but did not detect expression of epithelial sodium channel (ENaC) subunit genes, in agreement with previous studies, suggesting that renal and neuronal MR signaling have distinct mechanisms. Instead, aldosterone treatment increased expression of voltage-gated calcium channels (Cacna1d and Cacna1i), subunits of AMPA and kainate glutamate receptors (Gria1 and Grik4, respectively), and synapse-associated genes (e.g., Sv2c, Myrip, and Itpr1), consistent with increased activity of NTSHSD2 neurons. Notably, the gene with the most significant increase in expression was synaptic vesicle glycoprotein 2C (Sv2c), suggesting that aldosterone-MR signaling strengthens synaptic vesicle trafficking and exocytosis. Future studies will aim to determine the molecular mechanisms that drive aldosterone-mediated activation of NTSHSD2 neurons and its impact on sodium appetite. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Aldosterone-mediated salt appetite driven by hindbrain HSD2 neurons

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