Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 317, Issue 6, Pages F1623-F1636Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00264.2019
Keywords
adrenoceptors; blood pressure; norepinephrine; salt-sensitive hypertension; sodium-chloride cotransporter
Categories
Funding
- National Institutes of Health (NIH) [R56-AG-057687, R01-HL-139867, R01-HL-141406, R01-HL-107330, K02-HL-112718]
- American Heart Association [16MM32090001, 17GRNT33670023]
- NIH [R01-HL-139867, F31-DK-116501]
- Boston University's Undergraduate Research Opportunities Program
- American Society of Nephrology Foundation for Kidney Research Pre-Doctoral Fellowship
- American Physiological Society William Townsend Porter Physiology Development Fellowship award
- MERIT Award [I01BX002322]
Ask authors/readers for more resources
Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In saltresistant 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 alpha(1)- and/or beta-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 alpha(1)- and beta-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked saltsensitive 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 alpha(1)-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, beta-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, alpha(1)-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available