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.

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

“…WNK4 expression alone inhibits NCC (17,18,27,56) and does not result in stimulation of the Ste20-related proline alanine rich kinase−NCC cascade and Na + reabsorption (27). AII might also induce phosphorylation of WNKs, thereby modulating the activity of electrolyte flux pathways.…”

Surprisingly, traditional purple bamboo salt, unlike other salts does not induce hypertension in rats

“…Adrenergic receptor activation inhibits WNK4 expression and induces NCC expression, and it increases sodium retention in renal distal convoluted tubes. This increase of sodium retention leads to higher blood pressure in the end (Mu et al, 2011). We thus postulate that the inhibition of NCC expression by BS and PBS would be an autonomic nervous system independent mechanism.…”

“…Increase in NCC induces increase of sodium retention, and it is critical in the blood pressure increase. NCC expression in distal convoluted tubes is suppressed by WNK4 (Mu et al, 2011). To investigate the effects of BS and PBS on distal convoluted tubes' NCC mRNA expression, we performed the RT-PCR.…”

“…Hypertension is divided into primary or essential hypertension and secondary hypertension; primary hypertension is used to describe 90 -95% of the hypertension cases and occurs due to unclear medical causes, and secondary hypertension is the rest (5 -10%) of the cases and occurs due to clear medical causes (Carretero and Oparil, 2000). In terms of public health and social costs, hypertension contributes to the occurrence of stroke, myocardial infarction and kidney failure, and finally to death (Mu et al, 2011). A high salt or sodium intake is a major cause of hypertension.…”

‘Memory’ and ‘legacy’ in hypertension and lifestyle-related diseases

“…8 For example, an important recent study has shown that beta(2)-adrenergic stimulation causes inhibition of histone deacetylase-8 activity and suppression of WNK4, a regulator of sodium reabsorption. 9 Another study has suggested that statins may also cause epigenetic modification of multiple genes. 10 Taken together, these results suggest that multiple dynamic interactions between the genes and the environment, including biochemical, structural and epigenetic changes, may be involved in the mechanisms of the memory/legacy effect (Figure 1).…”