Editorial Commentary
Novel Gastro-Renal Axis and Sodium Regulation
During Hypertension
Anees Ahmad Banday, Mustafa F. Lokhandwala
See related article, pp XX–XX
H
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ypertension is one of the most prevalent multifactorial cardiovascular disorders caused by both genetic
and environmental factors. Overwhelming evidence shows
that abnormal sodium regulation because of either hereditary
factors or overconsumption of salt may lead to salt-sensitive
hypertension.1,2 Sodium regulation is complex mainly because
of its dependence on neuronal, hormonal, and local factors.1,2
Hormonal regulation involves a complex array of both natriuretic and antinatriuretic hormones affecting renal sodium
reabsorption.1,2 During normal sodium intake, antinatriuretic
hormones predominate whereby renin–angiotensin–aldosterone system maintains positive sodium balance by increasing
renal sodium absorption mainly because of the activation of
tubular sodium transporters.1,2 However, under sodium replete
conditions, natriuretic factors, such as dopamine, nitric oxide,
and arterial natriuretic peptide, inhibit renal tubular sodium
transporters, leading to increased sodium excretion.1,2 The kidney, especially the renal proximal tubule, which is responsible
for ≈60% of total renal sodium reabsorption, is critical in the
regulation of sodium balance.1,2 Reports from our laboratory
and others have shown that dopamine produced by the kidney is
critically involved in the excretion of an Na+ load.3,4 Dopamine,
via D1-like (composed of D1 receptor [D1R] and D5 receptor
subtypes) and D2-like receptors (composed of D2 receptor, D3
receptor, and D4 receptor subtypes), increases sodium excretion secondary to a decrease in the activity of renal sodium
transporters in several nephron segments, including the proximal tubules, thus preventing volume expansion and maintaining the blood pressure in the normal range.4 Chen et al3 have
shown that ≥50% of basal sodium excretion in moderately
volume expanded states is mediated by the paracrine action of
renal dopamine exerted on D1Rs. Dopamine, via D1R, inhibits
the activity of Na+/K+-ATPase in the basolateral membrane and
Na+/H+ exchanger 3 in the apical membrane of renal proximal
tubular cells.3,4 A defective D1R function is involved in the
pathogenesis of hypertension because it has been shown that
pharmacological blockade of dopamine receptors decreases
Na+ excretion and increases blood pressure.3,4 Decreased renal
dopamine production in the basal state or failure of dopamine
production to increase in response to an Na+ load has also been
reported in those with hypertension, prehypertension, and even
in those with a family history of hypertension in some ethnic
groups.5 Furthermore, inactivation of any dopamine receptor
gene in mice results in hypertension in mice.2
It is well established that an upregulation of antinatriuretic
factors or a downregulation of natriuretic factors disrupts the
renal sodium homeostasis and contributes to both salt-sensitive and salt-independent hypertension.1,2 However, apart from
neuronal role in sodium regulation, little is known about the
contribution of other organ systems to sodium homeostasis
or blood pressure regulation. This is despite the fact that salt
intake can modulate gastric hormone levels and an oral NaCl
load produces a much stronger diuresis and natriuresis than
an intravenous infusion of NaCl of similar magnitude.6 It is
reported that the natriuresis after ingestion of a certain amount
of Na+ may be caused by gastrin, an enterokine, secreted by G
cells in the stomach and duodenum and released into the circulation, which is taken up by renal cortical tubules to a greater
extent than the other enterokines released.6 Gastrin via cholecystokinin B receptor expressed in several nephron segments
decreases Na+ transport and regulates blood pressure because
mice lacking gastrin (ie, Gast−/−), systemically or only in the
gut, or functional gastrin receptors (eg, Cckbr−/−, cholecystokinin B receptor blockade) do not increase Na+ excretion after
an oral Na+ load and have increased blood pressure.7 Gastrin
is also important in salt sensitivity because Gast−/− mice on
low Na+ intake are normotensive but become hypertensive
with normal or high Na+ intake.8,9 Although several other gut
hormones (eg, cholecystokinin, uroguanylin) could potentially mediate natriuresis in response to an oral NaCl load
because it has been shown that a high NaCl intake increases
renal uroguanylin expression, oral sodium consumption may
not always increase circulating uroguanylin levels, and cholecystokinin is not taken up by renal tubules.10
The present study by Chen et al11 identifies a novel gastricrenal interaction using a genetic animal model of essential
hypertension. It is reported that gastrin needs a functioning
renal dopaminergic system because gastrin colocalizes with
the enzymes that synthesize dopamine, and Gast−/− mice
have decreased renal dopamine production. Also, inhibition
of dopamine synthesis prevents gastrin-induced natriuresis
of an oral Na+ load, despite functional gastrin receptor. This
study by Chen et al11 reconfirms the gastrin–dopamine links
by providing a potential mechanism at receptor level. They
also found a physical interaction between the proximal tubular D1R and gastrin receptor using the coimmunoprecipitation study. Treatment of proximal tubules from Wistar-Kyoto
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Heart and Kidney Institute, College of Pharmacy, University
of Houston, TX.
Correspondence to Mustafa F. Lokhandwala, Professor and Executive
Vice Dean for Research, 4800 Calhoun Rd, 453D SR 2 Bldg, Houston,
TX 77204. E-mail [email protected]
(Hypertension. 2013;62:00-00.)
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.113.01799
1
2 Hypertension December 2013
modulated by oxidative stress, whereas the renin–angiotensin–aldosterone system is positively regulated by oxidative
milieu. Taken together, the present study makes an important
contribution to our understanding of hormonal regulation of
renal sodium excretion by providing a novel gastric-renal
interaction involving gastrin–dopamine receptor signaling to
regulate sodium excretion and consequently blood pressure
during high sodium intake (Figure).
Sources of Funding
This work was supported, in part, by the National Institutes of Health
(grant number DK098509).
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Figure. Role of gastrin–dopamine axis in renal sodium excretion.
Sodium intake releases gastrin from stomach and duodenal
G cells causing a 10-to 20-fold increase in circulating gastrin.
Sodium also induces dopamine production in proximal
tubules. Gastrin, which is taken up by renal proximal tubule,
and dopamine activate respective receptors, which leads to
recruitment of more gastrin receptors (gastrin R) and dopamine
receptors (D1 receptor) to the cell membrane. The recruited
gastrin and dopamine receptors work synergistically to inhibit
basolateral sodium transporter Na/K-ATPase, which leads to
increased sodium excretion and prevents increase in blood
pressure.
rats with gastrin increased D1-like receptor expression in
the cell membrane, whereas fenoldopam, a D1R agonist,
increased gastrin receptor in the cell membrane. Thus, stimulation of one receptor increases the cellular distribution of
the other receptor into the cell membrane. This is physiologically relevant as blockade of D1 or gastrin receptors abolishes the fenoldopam-mediated increase in proximal tubular
cell membrane D1R and the gastrin-mediated inhibition of
Na+/K+-ATPase activity. Because spontaneously hypertensive rats have defective D1R, the inhibitory effects of gastrin and fenoldopam on Na+/K+-ATPase activity are lost, and
their synergism is no longer evident. It will be interesting
to study the molecular mechanism and signaling molecules
responsible for the synergistic inhibitory effect of gastrin and
D1R on sodium transporters. Also, studies investigating the
role of renin–angiotensin–aldosterone system may provide
a novel interaction between natriuretic and antinatriuretic
hormone mainly because increased sodium intake would suppress the renin–angiotensin–aldosterone system. It is also
worth mentioning that gastrin–dopamine system is negatively
Disclosures
None.
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Novel Gastro-Renal Axis and Sodium Regulation During Hypertension
Anees Ahmad Banday and Mustafa F. Lokhandwala
Hypertension. published online September 9, 2013;
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