Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension
Abstract
How high salt intake increases blood pressure is a key question in the study of hypertension. Salt intake induces increased renal sympathetic activity resulting in sodium retention. However, the mechanisms underlying the sympathetic control of renal sodium excretion remain unclear. In this study, we found that β(2)-adrenergic receptor (β(2)AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption. β(2)AR stimulation resulted in cyclic AMP-dependent inhibition of histone deacetylase-8 (HDAC8) activity and increased histone acetylation, leading to binding of the glucocorticoid receptor to a negative glucocorticoid-responsive element in the promoter region. In rat models of salt-sensitive hypertension and sympathetic overactivity, salt loading suppressed renal WNK4 expression, activated the Na(+)-Cl(-) cotransporter and induced salt-dependent hypertension. These findings implicate the epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension. The renal β(2)AR-WNK4 pathway may be a therapeutic target for salt-sensitive hypertension.
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In a rat model of salt-sensitive hypertension, stimulation of sympathetic signalling reduces expression of WNK4 owing to hyper-acetylation of its promoter.
“In a rat model of salt-sensitive hypertension, stimulation of sympathetic signalling led to reduced expression of a regulator of sodium reabsorption, protein kinase lysine-deficient 4 (WNK4), owing to hyper-acetylation of the promoter198.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [198]
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- Authors
- Mu, S., Shimosawa, T., Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D. S., Tanaka, H., & Fujita, T.
- Affiliations
- The University of Tokyo (JP)
- Yale University (US)
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Fujita, Toshiro
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-04-17
- Volume
- 17
- Issue
- 5
- Pages
- 573-580
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1985396932
- Cited by
- 236
- References
- 54
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 14 · 2023: 6 · 2022: 16 · 2021: 18 · 2020: 16 · 2019: 17 · 2018: 15 · 2017: 12 · 2016: 14 · 2015: 25 · 2014: 18 · 2013: 18 · 2012: 27
- FWCI
- 15.61
- Type
- journal article
- Language
- en
- Update notices
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23591213, 22590879)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- salt-sensitive hypertension, salt intake, beta2-adrenergic receptor, WNK4, glucocorticoid receptor, epigenetic regulation, HDAC8, histone acetylation, renal sodium reabsorption, NaCl cotransporter, renal sympathetic nerve activity, cAMP signaling, glucocorticoid response element, sodium retention
- MeSH terms
- Animals, Base Sequence, Blood Preservation, Histones, Hypertension, Kidney, Mice, Inbred C57BL, Models, Biological, Receptors, Glucocorticoid, Signal Transduction, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Sodium Chloride, Dietary, DNA Primers, Receptors, Adrenergic, beta-2, Mice, Knockout, Rats, Inbred Dahl, RNA, Small Interfering, Epigenesis, Genetic, Sodium Chloride Symporters, Mice, Rats
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