The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion
January
The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion
Xiaoliang Jiang 0 1
Wei Chen 0 1
Xing Liu 0 1
Zihao Wang 0 1
Yunpeng Liu 0 1
Robin A. Felder 0 1
John J. Gildea 0 1
Pedro A. Jose 0 1
Chuan Qin 0 1
Zhiwei Yang 0 1
0 1 Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC) , Beijing , P. R. China , 2 Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America, 3 Division of Nephrology, Departments of Medicine and Physiology, University of Maryland School of Medicine , Baltimore , Maryland, United States of America, 4 CollaborativeInnovation Center for Cardiovascular Disorders , Beijing , P. R. China
1 Editor: Eric Feraille, University of Geneva , SWITZERLAND
Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LEPM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.
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OPEN ACCESS
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: These studies were supported by grants
from National Natural Science Foundation (China)
(81370358, ZWY) and National Institutes of Health
(USA) (R01DK39308, PAJ).
Competing Interests: The authors have declared
that no competing interests exist.
Introduction
Hypertension occurs as a consequence of a complex interplay among multiple genetic,
epigenetic, and environmental determinants [
1
]. Salt consumption is an important non-genetic
determinant, and excessive dietary salt intake can increase blood pressure in genetically
susceptible individuals [
2
]. Recent population-based studies have revealed a nonlinear with even a
Jshaped correlation between salt intake and blood pressure or cardiovascular disease mortality
[
3–5
]. An increasing number of hormones, via their receptors, have been reported to regulate
ion exchangers, transporters, channels, and pumps in renal tubules, including the renal
proximal tubule (RPT), that are crucial in maintaining normal sodium balance [
6,7
].
Dopamine, secreted in the kidney mainly by RPT cells, via its receptors that are classified
into “D1-like” (D1R and D5R) and “D2-like” (D2R, D3R and D4R) receptors, is responsible for
over 50% of renal sodium excretion during conditions of mild volume and sodium excess [
8–
10
]. The acute infusion of fenoldopam, a D1-like receptor agonist, induces natriuresis and
diuresis in humans, rats, and mice [
8–14
]. Disruption of any of the dopamine receptor gene
subtypes in mice causes hypertension which can be aggravated by salt loading that is dopamine
receptor subtype dependent [
10
].
Gastrointestinal hormones have been reported to be involved in the regulation of renal
sodium excretion and blood pressure [
14,15
]. An oral sodium load causes a greater natriuresis
than an intravenous infusion of the same amount of sodium [
16–18
], suggesting that
gastrointestinal hormones have a role in regulating the postprandial natriuretic response. One such
hormone may be gastrin. Mice lacking the gastrin gene are hypertensive and salt-sensitive [18].
The receptor of gastrin (...truncated)