Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats

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.

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

“…Lee et al 2015). In a functional study, α1D-adrenoceptor expression (#) was found in non-microdissected renal cortex mRNA and linked to NCC regulation (Frame et al, 2019). +, represents lowest expression; +++, represents highest expression.…”

“…Norepinephrine stimulates NCC expression through an activation of basolateral Kir4.1/Kir5.1 potassium channel via beta-adrenergic receptor activation (Duan et al, 2019). Activation of α1-adrenoceptors inhibits the suppression of NCC during high salt intake via a WNK/SPAK/ OxSR1-dependent signaling pathway in rat kidneys (Frame et al, 2019). Dephosphorylation of NCC by the protein phosphatase 1 can be inhibited through a protein kinase A-dependent activation of the protein phosphatase 1 inhibitor via β1-adrenergic receptor activation (Penton et al, 2019).…”

“… Values are expressed as median reads per kilobase million (RPKM) with (+) being the lowest expression and (+++) being the highest expression of adrenoceptors (adapted from Lee et al, 2015 ). In a functional study, α1D-adrenoceptor expression (#) was found in non-microdissected renal cortex mRNA and linked to NCC regulation ( Frame et al, 2019 ). +, represents lowest expression; +++, represents highest expression.…”

Activation of the kidney sodium chloride cotransporter by the β2-adrenergic receptor agonist salbutamol increases blood pressure

“…In contrast, excessive SNS activity combined with a high NaCl intake limits this reduction in renal NaCl reabsorption and can lead to a substantial rise in blood pressure (BP). 2,3 High SNS activity stimulates numerous systemic factors that may raise BP, including the reninangiotensin-aldosterone system 4 and activation of adrenergic receptors (ARs) in renal tubular epithelial cells that can increase NaCl reabsorption. 5,6 The thiazide-sensitive Na þ Cl À cotransporter (NCC), expressed in the distal convoluted tubule (DCT), is essential for BP control as highlighted by loss-of-function NCC mutations underlying hypotensive Gitelman syndrome or activation of NCC in hypertensive pseudohypoaldosteronism type 2 (Gordon syndrome).…”

American Journal of Physiology-Renal Physiology Collections: Hypertension

“…In "Sympathetic regulation of NCC in norepinephrineevoked salt-sensitive hypertension in Sprague-Dawley rats" by Frame et al (5), the authors demonstrated the importance of considering the integrative nature of hypertension by determining the molecular pathway by which chronic norepinephrine (NE) signaling conveys salt sensitivity and increases Na + -Cl À cotransporter (NCC) activity. Under normal highsalt conditions, expression of NCC and NCC activators (with no lysine kinase 1, STE20/SPS1-related proline-alanine-rich kinase, and oxidative stress response 1) is suppressed; however, when combined with chronic NE exposure, this suppression does not occur.…”