Journal article
Aldosterone-induced salt appetite requires HSD2 neurons
JCI insight, Vol.9(23), e175087
12/06/2024
DOI: 10.1172/jci.insight.175087
PMCID: PMC11623954
PMID: 39446486
Abstract
Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.
Details
- Title: Subtitle
- Aldosterone-induced salt appetite requires HSD2 neurons
- Creators
- Silvia Gasparini - University of IowaLila Peltekian - University of IowaMiriam C McDonough - University of IowaChidera J A Mitchell - University of Iowa, NeurologyMarco Hefti - University of IowaJon M Resch - University of IowaJoel C Geerling - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.9(23), e175087
- DOI
- 10.1172/jci.insight.175087
- PMID
- 39446486
- PMCID
- PMC11623954
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- University of Iowa Aging, Mind, and Brian Initiative (AMBI)University of Iowa Department of NeurologyIowa Neuroscience InstituteCarver Trust
This work was supported by generous funds from the University of Iowa Aging, Mind, and Brian Initiative (AMBI); laboratory startup funds from the University of Iowa Department of Neurology; a Williams-Cannon Fellowship from the Iowa Neuroscience Institute; and an Early-Stage Investigator Award from the Carver Trust. We thank Andrew Thatcher for assistance with histology and cell-counting and Richard Palmiter for sharing Hsd11b2 -Cre mice. We also thank the University of Iowa Office of Animal Resources and Iowa Neuroscience Institute for providing space for continuous BioDAQ recordings in our mouse barrier facility, and the University of Iowa Metabolic Phenotyping Core for facilitating experiments in metabolic cages. Finally, we thank Jady Tolda for proofreading this manuscript.
- Language
- English
- Electronic publication date
- 10/24/2024
- Date published
- 12/06/2024
- Academic Unit
- Neurology; Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984738440302771
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