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.
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We thank K. Tamura (Yokohama City Medical University) for providing mDCT cells. Antibodies targeting NCC and p-NCC were provided by D.H. Ellison (Oregon Health and Science University) and S. Uchida (Tokyo Dental and Medical University), respectively. We also thank G. McMahon for his contribution to data discussion. Eplerenone and olmesartan were provided by Pfizer and Daiichi-Sankyo, respectively. This work was supported by research grants from the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (T.F.).
The authors declare no competing financial interests.
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Mu, S., Shimosawa, T., Ogura, S. et al. Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension. Nat Med 17, 573–580 (2011). https://doi.org/10.1038/nm.2337
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