Document Detail

Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension.
MedLine Citation:
PMID:  21499270     Owner:  NLM     Status:  MEDLINE    
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.
ShengYu Mu; Tatsuo Shimosawa; Sayoko Ogura; Hong Wang; Yuzaburo Uetake; Fumiko Kawakami-Mori; Takeshi Marumo; Yutaka Yatomi; David S Geller; Hirotoshi Tanaka; Toshiro Fujita
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-04-17
Journal Detail:
Title:  Nature medicine     Volume:  17     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-06     Completed Date:  2011-07-05     Revised Date:  2012-11-02    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  573-80     Citation Subset:  IM    
Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
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MeSH Terms
Base Sequence
Blood Preservation
DNA Primers / genetics
Epigenesis, Genetic
Histones / metabolism
Hypertension / etiology,  genetics*,  metabolism*,  physiopathology
Kidney / drug effects,  metabolism*
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  genetics,  metabolism*
RNA, Small Interfering / genetics
Rats, Inbred Dahl
Rats, Sprague-Dawley
Receptors, Adrenergic, beta-2 / metabolism*
Receptors, Glucocorticoid / antagonists & inhibitors,  deficiency,  genetics,  metabolism
Signal Transduction
Sodium Chloride Symporters / metabolism
Sodium Chloride, Dietary / administration & dosage,  adverse effects
Reg. No./Substance:
0/DNA Primers; 0/Histones; 0/RNA, Small Interfering; 0/Receptors, Adrenergic, beta-2; 0/Receptors, Glucocorticoid; 0/Sodium Chloride Symporters; 0/Sodium Chloride, Dietary; EC 2.7.1.-/Prkwnk4 protein, mouse; EC 2.7.1.-/Prkwnk4 protein, rat; EC Kinases
Comment In:
Cell Metab. 2011 Jun 8;13(6):619-20   [PMID:  21641543 ]
Nat Med. 2012 Sep;18(9):1324-5; author reply 1325-7   [PMID:  22961153 ]
Erratum In:
Nat Med. 2012 Apr;18(4):630
Nat Med. 2011 Aug;17(8):1020

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