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Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension

A Corrigendum to this article was published on 05 April 2012

A Corrigendum to this article was published on 04 August 2011

This article has been updated

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.

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Figure 1: Effects of salt loading on blood pressure, renal WNK4 and NCC expression in norepinephrine (NE)-infused C57BL/6j, β1AR-knockout (β1-KO) and β2AR-KO (β2-KO) mice.
Figure 2: Effects of isoproterenol (Iso), hydrochlorothiazide (HCTZ) and ICI118551, a β2-specific antagonist, on UNaV, plasma volume (PV) and blood pressure in rats fed a high-salt diet (HS).
Figure 3: Role of glucocorticoid receptor (GR) in Iso-induced WNK4 inhibition and blood pressure elevation.
Figure 4: Effects of Iso on nuclear GR protein and histone modulation of WNK4 transcription.
Figure 5: Effects of Iso treatment on HDAC8 activity and H3 and H4 acetylation in the WNK4 promoter region.
Figure 6: Renal NE turnover, renal WNK4 expression and mean arterial pressure in DOCA-salt rats and salt-loaded Dahl-S and Dahl-R rats.

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Change history

  • 04 August 2011

     In the version of this article initially published, the authors made several inadvertent errors during manuscript preparation. In Figure 3f the trace for WT mice was incorrect, and in Figure 4a the bands shown for 'Total GR' were incorrect. These errors did not affect the quantification of band intensities shown in Figure 4a and did not affect any of the conclusions of the article. The errors have been corrected in the HTML and PDF versions of the article.

  • 05 April 2012

     In the version of this article initially published, the image of the actin bands shown in Supplementary Figure 2b was mistakenly rotated 180 degrees. The image has been replaced with the bands in their correct orientation, and the densitometry shown for this blot has been recalculated, which does not affect the conclusions. The figure legends for Figure 1e and Supplementary Figure 2b have also been edited to indicate that the same kidney samples were used for the blots in Figure 1b,e and Supplementary Figure 2b and that the actin bands shown for these blots are identical.

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Acknowledgements

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.).

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S.Y.M. carried out both in vitro and in vivo experiments and wrote the manuscript during a PhD course under the direction of T.F. at the University of Tokyo; T.S. carried out in vivo experiments and conducted experiments; S.O., H.W., Y.U., F.K.-M., Y.Y. and T.M. helped with experimental procedures and contributed to data discussion; D.S.G. generated distal nephron-specific glucocorticoid receptor–knockout mice and H.T. provided glucocorticoid receptor plasmids and contributed to data discussion. T.F. designed and directed the project and wrote the manuscript.

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Correspondence to Toshiro Fujita.

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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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