In:
Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
Abstract:
The homeostatic control of blood pressure hinges upon the delicate balance between pro-hypertensinogenic (e.g., sympathetic nervous system) and anti-hypertensinogenic systems (e.g., dopamine system). The D 1 -like dopamine receptors (D 1 R and D 5 R) and the α 1A adrenergic receptor (ARα 1A ) are endogenously expressed in the renal proximal tubules and engender opposing effects on sodium transport, i.e., natriuresis (D 1 R and D 5 R) or anti-natriuresis (ARα 1A ). We tested the hypothesis that the D 1 R and D 5 R interact with and regulate the ARα 1A in human renal proximal tubule cells (hRPTCs) and in mice. We found that the D 1 R and D 5 R colocalized with the ARα 1A in hRPTCs and in proximal tubules in human kidney sections. Both receptors immunoprecipitated, pulled-down, and co-fractionated with ARα 1A in lipid rafts. Short-term co-treatment with fenoldopam (1 μM, 15 min) reversed the ARα 1 agonist phenylephrine (10 μM, 15 min)-induced Na + ,K + -ATPase (NKA) translocation from the cytosol to the plasma membrane in hRPTCs (plasma membrane NKA: vehicle=100±5% vs. fenoldopam=65±3% vs. phenylephrine=177±5% vs. co-treatment=115±7%; P 〈 0.05, n=3-4). Long-term fenoldopam (1 μM, 24 hr) treatment resulted in decreased D 1 R (70.0±5.9%, P 〈 0.05, n=3) and D 5 R (50.1±10.7%, P 〈 0.05, n=3), consistent with D 1 -like receptor desensitization, but increased ARα 1A abundance (142.6±4.3%, P 〈 0.05, n=3) in hRPTCs. RNAi silencing of ARα 1A (48 hr) increased the expression of D 1 R and D 5 R. To determine the extent of regulation of each D 1 -like receptor on ARα 1A , we used the subclass-selective ARα 1 agonist phenylephrine (5 μg/kg body weight, i.p.) and the receptor-specific ARα 1A agonist A610603 (25 ng/kg body weight, i.p.) to inhibit Na + excretion in three mouse strains. Phenylephrine treatment resulted in 59.6%, 84.2%, 99.3%, and 99.5% reduction from basal level of 24-hr Na + excretion_while A61603 treatment resulted in 42.4%, 67.1%, 99.9%, and 100% reduction_in wild-type controls, D 1 R -/- , and D 5 R -/- knockout mice, and D 1 R/D 5 R -/- double knockout mice, respectively, suggesting a stronger regulatory effect of D 5 R on ARα 1A . Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems.
Type of Medium:
Online Resource
ISSN:
0194-911X
,
1524-4563
DOI:
10.1161/hyp.62.suppl_1.A468
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2013
detail.hit.zdb_id:
2094210-2
