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- Title
Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension.
- Authors
ShengYu Mu; Shimosawa, Tatsuo; Ogura, Sayoko; Hong Wang; Uetake, Yuzaburo; Kawakami-Mori, Fumiko; Marumo, Takeshi; Yatomi, Yutaka; Geller, David S.; Tanaka, Hirotoshi; Fujita, Toshiro
- 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 β2-adrenergic receptor (β2AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption. β2AR 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 β2AR-WNK4 pathway may be a therapeutic target for salt-sensitive hypertension.
- Subjects
HYPERTENSION; PHYSIOLOGICAL effects of sodium; BLOOD pressure; ADRENERGIC receptors; HISTONE deacetylase; GLUCOCORTICOID receptors
- Publication
Nature Medicine, 2011, Vol 17, Issue 5, p573
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.2337