J Am Soc Nephrol 14: 2688–2689, 2003
Commentary on. . .Neuronal Nitric Oxide Synthase: Its Role
and Regulation in Macula Densa Cells
SCOTT THOMSON
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Department of Medicine, Division of Nephrology-Hypertension, University of California; and VA San Diego
Health Care System, San Diego, California
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The macula densa control of renin secretion and tubuloglo-
merular feedback (TGF) both occur in the juxtaglomerular
apparatus (JGA) of nephrons. The renin-angiotensin system
has basked in attention for 2 decades, while TGF remains
arcane to all but those who study it. Nonetheless, the body’s
internal environment is regulated, in large part, by these two
systems.
A decade ago, Wilcox and colleagues (1) identified nitric
oxide synthase (NOS) I in the macula densa. This discovery
spawned interest and experimentation. Subsequently, a sound
consensus emerged that NO from the macula densa suppresses
the TGF response. There is a weaker consensus that NO from
the macula densa can stimulate renin secretion. It has been
difficult to demonstrate a major consequence of NO-dependent
renin secretion. In contrast, physiologic relevance of macula
densa NOS as a modulator of TGF is easier to postulate and to
prove. This is because NO from the macula densa shifts the
TGF response rightward and makes it less steep (2). When
macula densa NOS I is active, there will be increased distal salt
delivery for any given GFR and increased GFR for any given
distal salt delivery. The importance of this is revealed by
positive salt balance and increased BP that gradually ensue
when macula densa NOS I is inhibited (3).
There are likely multiple determinants of macula densa NOS
I activity. On the basis of the ubiquity of homeostasis-as-
negative-feedback throughout physiology, one can expect each
determinant of macula densa NO will also be affected by NO
so as to serve the cause of homeostasis. To understand the role
of macula densa NOS I in physiology, it is important to learn
what affects it and what is affected by it. It is also important to
quantify these relationships to predict the outcome when they
come into conflict.
The present study by Kovacs et al. (4) provides new infor-
mation about certain effectors and affectors of macula densa
NOS I. First, these studies confirm that NO from the macula
densa suppresses apical Na:2CL:K transport in the same cell.
Sodium entry via this symporter is the first step en route to
TGF-mediated vasoconstriction, and reduced Na:2Cl:K sym-
Correspondence to: Scott C. Thomson, MD, University of California and
VAMC, 3350 La Jolla Village Drive, San Diego, CA 92161-9151. Phone:
858-552-7528; Fax: 858-552-7549; E-mail: sthomson@ucsd.edu
1046-6673/1410-2688
Journal of the American Society of Nephrology
Copyright © 2003 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000091809.15383.77
port is a leading candidate to explain how NO pushes the TGF
response rightward, influencing GFR, distal salt delivery, and
BP. Others have inhibited Na:2Cl:K symport using exogenous
NO donors in Henle’s loop (5), but this is the first demonstra-
tion that endogenous NO can have this effect. These authors
also confirm that NO from the macula densa diffuses as far as
the vascular pole of the glomerulus, where it could act as a
paracrine vasodilator to oppose the influence of all locally
active vasoconstrictors, including TGF.
Is there a way to distinguish between the autocrine (trans-
port) and paracrine (vasodilator) effects of macula densa NO as
a modulator of TGF? A future approach might be to eliminate
the autocrine effect by permeabilizing the macula densa to salt
and then determining whether the TGF response to tubular salt
is still being modulated by NOS I activity. Another way might
become available if someone discovers that the autocrine effect
of NO in the macula densa is not mediated by cGMP, because
cGMP mediates the overall effect of NO on TGF (6).
A second finding of Kovacs et al. (4) is the converse of the
first, and pertains to the effect of intracellular sodium on NOS
I activity in the macula densa. The possibility that increased
cell sodium activates NOS is important for two reasons. First,
combining an inhibitory effect of NO on sodium entry with a
positive effect of cell sodium on NO formation would consti-
tute a negative feedback system for stabilizing the macula
densa cell. If either of these elements is missing, then macula
densa NOS I cannot be considered in this role. Second, if
macula densa NOS is activated by cell sodium, this could
explain how NOS I contributes to the rightward resetting of
TGF that normally occurs during a prolonged increase in salt
delivery to the distal nephron. Kovacs et al. (4) are the second
group to measure the effect of macula densa salt on NO
production. Recently, Liu et al. (7) reported that macula densa
NO is salt-dependent. Now, Kovacs et al. (4) do likewise, with
one critical caveat, namely that the salt stimulus required to
elicit NO is supraphysiologic and may not be relevant to daily
life.
If we discard the possibility that macula densa salt normally
stimulates NOS I activity as the present findings suggest, then
ongoing efforts to explain how the sensitivity of TGF is reg-
ulated through events in the JGA become complicated. Those
efforts have led us to theorize that NO provides an intermediate
link between steady state salt delivery and the amount of salt
required to elicit a TGF response. The supporting data for this
are complex and eclectic, but one simple observation is worth
noting, namely that the vasoconstrictor response to NOS I
 J Am Soc Nephrol 14: 2688–2689, 2003
blockade is usually greater when there is more salt being
delivered to the macula densa (1– 6). The simplest route to this
end would be for NO formation to vary in proportion to
physiologic changes in macula densa salt. The present findings
call this into question, but one might reconcile these data, the
opposite finding from Liu et al. (7), and the micropuncture data
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from various labs (1, 6) by making the reasonable supposition
that there are sodium-dependent and sodium-independent path-
ways competing for control of NOS I in the macula densa and
that circumstances can arise where one or the other dominates.
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In fact, we observed this in micropuncture experiments where
NOS I activity was dominated by macula densa salt in normal
rats, but not in rats with streptozotocin diabetes (unpublished
observation).
A third observation of Kovacs et al. (4) is that angiotensin II
(AngII) does not directly affect NO formation in macula densa
cells. This is an important direct observation in light of the
abundance of phenomenologic data published over the years
that stresses AngII–NO interactions in the kidney. However,
this negative finding is not necessarily a surprise given that
there are models of increased macula densa NOS I expression
that run the gamut of renin-angiotensin activities.
Kovacs et al. (4) demonstrate the ability to record important
signaling events in the anatomically complex JGA with broad
implications for kidney function and salt balance. No doubt,
more of this type of information will be forthcoming that could
never be revealed by cultured cells or histologic examinations.
See related article, “Neuronal Nitric Oxide Synthase: Its Role and Regulation in Macula Densa Cells,” on pages 2475–2483.
Neuronal Nitric Oxide Synthase 2689
Acknowledgments
This work was supported with funds from the National Institutes of
Health (RO1 DK565248 and RO1 DK28602) and the by the Depart-
ment of Veterans Affairs Research Service.
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