Abstract
Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl- cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.
Highlights
Dietary Naϩ intake plays a significant role in blood pressure regulation, as increased Naϩ retention is a well-established precursor of hypertension [15, 27, 44]
Dietary Naϩ-evoked suppression of Naϩ-ClϪ cotransporter (NCC) activity in saline-infused rats was paralleled by reductions in NCC mRNA, protein expression, and phosphorylation at Thr53 (Fig. 1, C and D, Fig. 2, and Fig. 3A)
NE-infused rats fed a normal salt (NS) diet exhibited an increase in blood pressure (MAP: 149 Ϯ 4 mmHg in the NS ϩ NE group vs. 122 Ϯ 2 mmHg in the NS ϩ saline group, P Ͻ 0.05) that occurred independently of alterations in NCC activity, expression, or phosphorylation (Fig. 1, A–D)
Summary
Dietary Naϩ intake plays a significant role in blood pressure regulation, as increased Naϩ retention is a well-established precursor of hypertension [15, 27, 44]. Given that salt sensitivity is driven partly by a sympathoexcitatory response to dietary Naϩ intake [7, 34] that drives Naϩ retention, there is a pivotal role of the kidney in the pathophysiology of salt-sensitive hypertension. In saltresistant Sprague-Dawley rats, increased dietary salt intake suppresses sympathetic outflow and circulating NE levels [16, 17, 41] and persistently reduces NCC expression and activity [31, 43]. NE infusion during normal salt (NS) intake appears to evoke a species-specific NCC response with no alteration in NCC expression in Sprague-Dawley rats [33, 43] versus an increase in total and phosphorylated NCC in C57Bl/6J mice [25, 39]
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