concerted actions of renal endothelial and macula densa no systems in the maintenance of...

Concerted actions of renal endothelial and macula densa

NO systems in the maintenance of extracellular ¯uid

volume

B . B R A A M , E . T U R K S T R A and H . A . K O O M A N S

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands

ABSTRACT

It is now clear that nitric oxide (NO) exerts a substantial influence on renal function and that the kidney

has a high capacity to produce NO. However, there are at least two different NO systems in the kidney.

The interplay between NO generated by the endothelium and by the macula densa is considered in this

review. It seems that endothelial NO increases in response to an increase in perfusion pressure and an

increase in distal delivery, whereas macula densa NO decreases upon a sustained increase in distal

delivery. Furthermore, evidence is accumulating that macula densa NO may well mediate renin release.

Though seemingly in contrast, both the response of the endothelial NO and of the macula densa NO

system seem appropriate to restore a perturbation of fluid balance. The function of the tubuloglomerular

feedback (TGF) mechanism is likely to be influenced by both sources of NO, because of the close

proximity of these NO producing cells to the vascular smooth muscle cells of the afferent arteriole. The

endothelial NO system seems to be responsible for short-term, dampening actions to increased

afferent arteriolar tone elicited by activation of the TGF system. The macula densa NO system, on the

other hand, is probably adapting TGF responses to sustained increases in distal delivery. The analysis

presented in this paper is an attempt to integrate the function of the two NO systems into physiological

regulation. The exact role of the medullary NOS enzymes remains to be further elucidated.

Keywords angiotension, autoregulation, extracellular ¯uid volume, nitric oxide synthase, renal

function, tubuloglomerular feedback.

Received 14 October 1999, accepted 29 October 1999

There is now abundant evidence that nitric oxide (NO)

controls many physiological processes, such as neuro-

transmission and vasomotion. Blockade of NO synth-

esis using L-arginine derivatives leads to severe

hypertension with end-organ damage in the kidney

(Baylis et al. 1992, Ribeiro et al. 1992, Verhagen et al.

1998). As a consequence, numerous studies have been

directed towards elucidation of the actions of NO on

renal haemodynamic and reabsorptive function. These

studies indicate generally that NO leads to renal vaso-

dilation and has natriuretic properties. All three NOS

enzymes are present within the kidney and widely

distributed throughout the different structures. In

detail, there remain several uncertainties on the actions

of NO, in particular concerning the interaction between

the NO and renin±angiotensin system and concerning

the contribution of the different NO synthases to

overall regulation of renal function. In this paper, we

formulate a model on extracellular ¯uid volume

(ECFV) regulation in an attempt to integrate the

functions of renal endothelial and macula densa NOS

enzymes and the renin±angiotensin system. Remark-

ably, the analysis reveals that despite the opposite

responses of endothelial and macula densa NOS to

perturbations of the ECFV, the responses seem

appropriate to facilitate normalization of the ECFV.

Many uncertainties on the function of inducible NOS

in the kidney still remain, and the discussion of NO

synthesis in this paper will be limited to endothelial

(e-NOS) and neuronal (n-NOS) synthases.

FEATURES OF ENDOTHELIAL NOS

The gene for endothelial NOS is located on chromo-

some 7 on the human genome. The promoter region is

capable of binding many transcription factors such as

AP-1, AP-2, NF-1, NF-j-B and cAMP and shear

stress response elements (Forstermann et al. 1998,

Correspondence: Branko Braam MD PhD, Department of Nephrology and Hypertension ± F03.226, University Medical Center Utrecht,

PO Box 85500, 3508 GA Utrecht, the Netherlands.

Acta Physiol Scand 2000, 168, 125±132

Ó 2000 Scandinavian Physiological Society 125

Karantzoulis-Fegaras et al. 1999). The active enzyme is

located within the cell membrane, and is closely asso-

ciated with caveolae (Feron 1999). The function of the

enzyme is probably highly related to the binding of

caveolin. Besides NO, the enzyme has the potential to

form superoxide; the ratio between NO and superoxide

formation of the enzyme is closely coupled to the

binding of the co-factor tetra-hydro-biopterin (BH4)

(Vasquez-Vivar et al. 1998). At present, not much is

known about the exact regulatory processes that

underlie the travelling of e-NOS and caveolin to the cell

membrane, particularly in disease states (Feron 1999).

The enzyme is calcium/calmodulin-dependent (Fors-

termann et al. 1998). There are reports that the enzyme

is closely associated with calcium channels, and that the

integrity of the caveolae is essential for calcium in¯ux

and activation of NO production by e-NOS (Feron

et al. 1998). Shear stress, angiotensin II, several growth-

promoting factors and oestrogen have been shown to

enhance the transcription of e-NOS (Forstermann et al.

1998), and oxidized low-density lipoprotein and oxygen

tension are associated with downregulation of the

enzyme. The exact regulatory pathways have only been

partially resolved. From these factors, shear stress and

pressure stretch are probably the most powerful

modulators of e-NOS gene expression (Busse &

Fleming 1998).

ENDOTHELIAL-DERIVED NO AND

ALTERATIONS IN PERFUSION

PRESSURE AND ANG II ACTIVITY

The myogenic mechanism is the intrinsic property of

the preglomerular vasculature to react to an increase in

perfusion pressure with a decrease in diameter

(Schnermann et al. 1984, Navar 1998). The pathway

mediating this myogenic mechanism probably involves

activation of calcium-channels by shear stress and

pressure stretch sensitive transmembrane proteins

(Davies & Tripathi 1993, Malek & Izumo 1994). The

importance of mobilization of extracellular calcium is

illustrated by experiments that failed to show renal

autoregulation during administration of calcium-entry

blocking agents (Loutzenhiser et al. 1987, Mitchell &

Navar 1990, Carmines et al. 1992, Huang et al. 1994).

Coinciding with the activation of the myogenic mech-

anism is activation of e-NOS by increased shear stress

and pressure stretch. Thus, one could imagine that NO

release by endothelial cells antagonizes the vasocon-

strictive actions of calcium in¯ux into vascular smooth

muscle cells, and thus oppose the renal autoregulatory

response.

Studies in the isolated perfused hydronephrotic

kidney preparation and in the juxtamedullary nephron

preparation have provided support for this hypothesis.

Two studies demonstrated that autoregulatory adjust-

ments, i.e. vasodilation in response to decreases in

perfusion pressure, were enhanced during non-selective

inhibition of NO synthesis (Imig and Roman 1992,

Hayashi et al. 1995). In isolated afferent arterioles, pres-

sure-induced vasoconstriction was more pronounced in

non-perfused as compared with perfused arterioles

(Juncos et al. 1995). Both disruption of the endothelium

as well as blockade of NO synthesis augmented the

vasoconstriction in the perfused afferent arterioles

(Juncos et al. 1995).

The tubuloglomerular feedback (TGF) system is a

control system that stabilizes early distal tubular ¯uid

and solute delivery (distal delivery) by increasing

afferent arteriolar resistance upon an increase in distal

delivery. The responsiveness of the system is dependent

upon several humoral factors, such as angiotensin II

(Braam et al. 1994). With regard to the dynamic control

of glomerular capillary pressure by the TGF system,

several groups have now demonstrated that systemic,

proximal tubular and peritubular capillary administra-

tion of NOS blockers enhances the TGF system

(Wilcox et al. 1992, Thorup et al. 1993, Ito & Ren 1993,

Thorup & Persson 1994, Braam & Koomans 1995a, b,

Kawata et al. 1996, Thorup & Persson 1996). This

indicates that under physiological conditions NO exerts

a depressing in¯uence on TGF responsiveness, which

will also offset autoregulatory responses of the vascu-

lature.

In view of the mentioned experiments, it is some-

what surprising that at the whole kidney level, obser-

vations are less consistent. A positive relation between

perfusion pressure and NO activity in the renal cortex

has been reported, as assessed with a NO-sensitive

electrode and urinary NO2/NO3 excretion (Majid et al.

1998). The same group, however, failed to show

improvement of autoregulation of renal blood ¯ow

(RBF) and glomerular ®ltration rate (GFR) during NOS

inhibition in dogs (Majid & Navar 1992). In experi-

ments in the cortex and medulla of Munich±Wistar rats,

the autoregulatory index was enhanced by NOS inhi-

bition in the medulla, however, not in the cortex

(Madrid et al. 1997). In experiments in our laboratory,

we have applied a mathematical analysis to assess ef®c-

acy of RBF autoregulation before and during inhibition

of NOS in normotensive and two-kidney, one-clip

Goldblatt hypertensive rats. During L-NNA adminis-

tration in normotensive rats, the autoregulatory ef®cacy

increased at lower perfusion pressures, however, the

lower limit of autoregulation did not change. In the

Goldblatt rats, autoregulation under control conditions

was impaired and administration of L-NNA resulted in

increased autoregulatory ef®cacy and a decrease in the

lower limit of autoregulation (Turkstra et al. 2000). A

recent study by Just et al. (1999) investigated transfer

126 Ó 2000 Scandinavian Physiological Society

Actions of renal endothelial and macula densa NO systems � B Braam et al. Acta Physiol Scand 2000, 168, 125±132

functions of RBF in dogs in the presence and absence

of a functional NO system. The gain of the function

was enhanced during NO blockade at frequencies

above 0.08 Hz. The authors suggested that under

physiological conditions NO may buffer the RBF

modulation of the myogenic response and thereby

prevent resonance. Despite the controversies, the

above-mentioned data support that under certain

circumstances NO impairs autoregulation.

The interaction between Ang II and NO has been

approached using different designs of experiments. In

the isolated perfused afferent arteriole Ito et al. (1991)

demonstrated increased sensitivity to the vasocon-

strictive actions of Ang II during NOS inhibition.

During angiotensin-converting enzyme (ACE) inhibi-

tion and AT1 receptor blockade, the vasoconstriction

caused by NO inhibition has been shown to be

decreased at the microvascular level (Ohishi et al.

1992). In our laboratory, the concomitant infusion of

Ang II and L-NNA into peritubular capillaries resulted

in a dramatic decrease in stop-¯ow pressure, a

measure of glomerular capillary pressure, whereas the

infusion of either compound alone did not (Braam &

Koomans 1995a). At the whole kidney level, similar

results have been obtained. In two studies, the vaso-

constrictive actions of Ang II were enhanced during

NOS inhibition (Baylis et al. 1994, Schnackenberg et al.

1995). In rats that were acutely administered with a

low dose of L-NNA intravenously, RBF increased

towards control levels upon acute application of the

AT1 receptor antagonist losartan. remarkably, in rats

that were infused a high dose of L-NNA, acute AT1

receptor antagonism failed to affect RBF (Turkstra

et al. 1998a). Similarly, the actions of systemic

L-NAME infusion were not different in rats pretreated

with the ACE inhibitor or with losartan as compared

with untreated animals (Baylis et al. 1993). These data

indicate that Ang II does not mediate the renal

vasoconstrictive actions of NOS inhibition, however,

NO buffers the vasoconstrictive actions of Ang II.

Thus, acute variations in Ang II activity are paralleled

by acute changes in NO activity.

Taken together, both pressure and Ang II activity

share a positive relationship with endothelial NO

activity. This implicates that under conditions of high

pressure, the e-NOS will be activated by shear stress

and pressure stretch, leading to relative vasodilation,

which will facilitate pressure natriuresis. In line with this

view are experiments that show that pressure natriuresis

is impaired during NOS inhibition (Alberola et al. 1992,

Krier & Romero 1998). On the other hand, the increase

in Ang II activity during low perfusion pressure also

leads to activation of e-NOS. In this state, the enhanced

NO formation will protect the kidney from excessive

vasoconstriction by Ang II. The latter situation has not

been the subject of speci®c research and needs further

exploration.

FEATURES OF THE MACULA DENSA

NOS

The complex gene coding for n-NOS is present on

chromosome 12 on the human genome (Forstermann

et al. 1998). Unlike e-NOS, several transcripts have

been detected in different organs. NOS transcripts in

the kidney have a speci®c exon (Oberbaumer et al.

1998). Like e-NOS, the promoter regions of the n-NOS

gene probably have the potential to bind numerous

transcription factors (Forstermann et al. 1998). Within

the kidney, the enzyme is mainly localized within the

macula densa cells (Mundel et al. 1992, Bachmann et al.

1995, Bosse et al. 1995, Kihara et al. 1997, Wilcox &

Welch 1998), where it can be found in small vesicles

(Tojo et al. 1994). Nevertheless, the enzyme has also

been detected in the renal medulla, in several tubule

segments (Terada et al. 1992, Ahn et al. 1994, Wang

et al. 1998) and in nitrinergic nerve terminals (Bach-

mann et al. 1995). Like e-NOS the enzyme is dependent

upon calcium/calmodulin and BH4 (Forstermann et al.

1994). Expression of the enzyme in the macula densa is

downregulated by sodium loading, although the exact

pathways are unclear at present (Bosse et al. 1995,

Schricker et al. 1996, Singh et al. 1996). Regulation of

the medullary isoform of n-NOS is functionally

different, in that sodium loading has been associated

with an increase in n-NOS expression in the medulla

(Mattson & Higgins 1996).

MACULA DENSA NOS AND DISTAL

DELIVERY

Although many questions remain about the detailed

pathways involved, macula densa n-NOS expression

seems to be closely and negatively coupled to changes

in distal tubular ¯uid and solute delivery. Two studies

have been published that show enhanced expression of

n-NOS in rats treated with furosemide for several days

(Bosse et al. 1995, Schricker et al. 1996). Renin expres-

sion was upregulated in parallel in one study (Bosse

et al. 1995), while other studies showed the absence of

any signi®cant changes in e-NOS (or i-NOS) expres-

sion in the kidney (Schricker et al. 1996). In line with

these ®ndings is a study that evaluated angiotensinogen,

renin and n-NOS expression in renal cortical slices of

rats maintained on a low, normal and high sodium diet.

In this study, the expression of all three factors was

negatively correlated with the amount of sodium in the

diets (Singh et al. 1996). Further support for the

hypothesis that renin release and n-NOS are regulated

in parallel is provided by experiments employing AT1a


Acta Physiol Scand 2000, 168, 125±132 B Braam et al. � Actions of renal endothelial and macula densa NO systems

receptor-de®cient mice, which show both increased

n-NOS and renin mRNA levels. Remarkably, in the

absence of AT1 receptor-mediated activity, both

n-NOS and renin mRNA remained responsive to

sodium loading (Kihara et al. 1998).

In studies in dogs, it was reported that the increase

in renin release during decreases in renal perfusion

pressure was attenuated during non-selective NOS

inhibition (Persson et al. 1993). The increase in renin

release during furosemide administration was inhibited

in in vivo experiments in rats by the relatively selective

n-NOS inhibitor 7-nitro-indazole, whereas this

compound failed to affect the increase in renin release

during decreases in renal perfusion pressure (Beier-

waltes 1995). He and Greenberg attempted to separate

the in¯uence of NO generated by the endothelium

from the NO generated within the macula densa itself.

Addition of non-selective NOS inhibitor to the perfu-

sion ¯uid of the isolated perfused rabbit juxtaglomerular

apparatus with attached ascending limb reduced macula

densa renin release (He et al. 1995). Interestingly,

addition of the NO donor sodium nitroprusside also

reduced renin release (He et al. 1995). In a recent

review, the detailed pathways are explored that mediate

renin release (Schnermann 1998). Despite the fact that

these observations seem controversial, one can detect

unexpected logic when evaluating the response to

changes in extracellular ¯uid volume. In this situation,

perfusion pressure will slightly increase and activate

e-NOS. NO generated by e-NOS will then diminish

renin secretion. The concomitant increase in distal

delivery under conditions of expansion of the extra-

cellular ¯uid volume will diminish renin release also.

Thus, the opposite response of both systems to an

increase in ECFV will lead to an adequate adaptation of

renin release (Fig. 1).

Summarizing, the activity of the macula densa NO

system seems to parallel renin release. It has been

proposed that NO generated within the macula densa

may mediate the formation of renin. The fact that NO

derived from e-NOS has opposite consequences for

renin release could be owing to the intracellular

arrangement of n-NOS in the macula densa cells. The

separate responses of e-NOS and macula densa n-NOS

enable the kidney to separate the in¯uence of changes

in perfusion pressure and changes in tubular reab-

sorption for renin release.

TUBLOGLOMERULAR FEEDBACK

MEDIATION AND NITRIC OXIDE

There are now many reports published that show that

systemic, proximal tubular or peritubular capillary

infusion of NOS inhibitors enhance TGF responses

(Wilcox et al. 1992, Ito & Ren 1993, Thorup et al.

1993, Thorup & Persson 1994, 1996, Braam &

Koomans 1995a, b, Kawata et al. 1996). In our labo-

ratory, we have shown that during ®xed renal NO

levels (intrarenal NO clamp experiments), TGF

responses are enhanced (Turkstra et al. 1998a, b, c).

This indicates that NO forms an integral part of the

TGF-loop, and is released upon TGF activation. At

this moment, there is substantial debate as to whether

n-NOS or e-NOS is the source for the modulatory

actions of NO on TGF. For both possibilities there

are hypothetical arguments. On the one hand, n-NOS

could be activated owing to enhanced calcium in¯ux

in macula densa cells, accompanying an acute increase

in distal delivery. On the other hand, e-NOS could be

activated due to enhanced shear stress in the afferent

arteriole as a consequence of vasoconstriction by the

TGF mediator. Despite the fact that there is as yet no

de®nitive answer to this issue, several experiments

have provided evidence for both hypotheses. TGF

responses have been shown to be enhanced by

intratubular infusion of the relatively selective n-NOS

inhibitor 7-NI, supporting a role for n-NOS. Never-

theless, augmentation of TGF responses by non-

selective NO blockade exceeded the augmentation

observed during 7-NI (Thorup & Persson 1996). It

should be noted that the chronic responses of macula

densa NOS to changes in sodium intake are not

compatible with a function of macula densa NOS in the

acute modulation or mediation of TGF responsiveness.

Other observations support a role for e-NOS. First, the

augmentation of TGF responses during peritubular

capillary infusion of L-NNA is almost instantaneous

(Braam & Koomans 1995b). Furthermore, we observed

that infusion of L-NNA into a neighbouring nephron

proximal tubule augmented the TGF responses of the

nephron under study, indicating that L-NNA was able to

leave the tubular lumen, and cause augmentation of

TGF in supposedly very low concentration (Braam &

Koomans 1995b).

This issue on the source of NO can only be

resolved when selective e-NOS and n-NOS blockers

would be available. Up to now, the data support that

both NO systems could contribute to TGF modu-

lation. The proximity of the afferent arteriole to both

Figure 1 Response of the endothelial and macula densa NOS to

extracellular ¯uid volume (ECFV) expansion. Both the increase in

e-NOS activity and the decrease in macula densa n-NOS activity will

result in an appropriate decrease in renin release.



the macula densa and endothelial source of NO

brings the option that both sources contribute to the

function of the TGF system. In view of the analysis

of the endothelial and macula densa NO system as

presented above, it could be anticipated that the

endothelial NO system mediates an acute dampening

of the TGF system particularly under conditions of

high shear stress and under conditions of high Ang

II levels. The macula densa NO system, on the other

hand, could well participate under conditions of low

distal delivery. However, this system is probably not

participating in acute mediation of TGF responses,

but has a chronic modulatory in¯uence, mainly

mediated by mediating renin release. Taken together,

this would imply that under physiological conditions,

both systems participate in TGF mediation, and that

the contribution of the individual systems depends

upon the prevailing distal delivery, Ang II levels and

shear stress within the afferent arteriole. This repre-

sentation of NO-dependency of the TGF system is

depicted in Fig. 2.

CONCERTED RESPONSE OF

ENDOTHELIAL AND MACULA DENSA

NO SYSTEMS TO CHANGES IN

EXTRACELLULAR FLUID VOLUME

The analysis of these two major NO systems leads to

the concept that the systems differ substantially

regarding their regulation. The endothelial NO system

seems to be a fast-responding adaptive mechanism,

which functions to respond to acute changes in renal

perfusion pressure, and buffers the actions of Ang II.

The macula densa NO system, on the other hand,

seems to adapt to long-term changes in sodium intake

and consequent changes in distal delivery. Its main

function may well be the regulation of renin formation

and release. Despite the ongoing debate on this issue,

both systems could well contribute to the actions of

NO on the TGF system, which functions as a counter-

mediator, dampening the TGF response. The proper-

ties of both systems are summarized in Table 1. Both

systems will contribute to the maintenance of ECFV.

Figure 2 (a) Acute increases in distal

tubular ¯ow and solute delivery will

activate e-NOS and dampen the TGF

response. Chronic changes in distal

tubular ¯ow and solute delivery will

modulate the impact of NO produced

by macula densa NOS on the TGF

responses, mainly elicited by a

decrease in renin release. (b) Both a

low and a high perfusion pressure will

be associated with high total NO

levels, however, the participation of

both NOS systems will be different.

Total NO will oppose the

vasoconstrictive actions of Ang II

under conditions of low perfusion

pressure.



The endothelial NO system will be activated upon

increases in perfusion pressure and shear stress and lead

to vasodilation and depression of the TGF response.

Furthermore, NO generated by the endothelium and

reaching the macula densa will decrease renin formation

and release. The macula densa NO system will deacti-

vate upon sustained increases in distal delivery, which

also results in a decrease in renin formation and release.

This paper focuses on the endothelial and macula

densa NO systems, while there is substantial evidence

that also the medullary NO systems importantly

contribute to the regulation of sodium excretion. All

of the NOS enzymes have been detected within the

renal medulla, are widely distributed and display

increased expression upon sodium loading. One report

investigated the actions of aminoguanidine, which has

been used as a selective i-NOS inhibitor, on blood

pressure and calcium-dependent and -independent

NOS activity in the renal medulla. The compound did

not affect RBF and mean arterial pressure when

administered acutely, however, during chronic infu-

sion, mean arterial pressure increased and calcium-

independent NOS activity decreased (indicating

adequate inhibition of i-NOS). These data illustrate

that there may well be a complex synergism between

the endothelial NO system in regulating RBF and

medullary NOS systems in mediating pressure

natriuresis. The extent to which endothelial NO and

the medullary NOS systems participate, in pressure

natriuresis has not yet been resolved.

CONCLUSION

Two functionally different NO systems in the kidney,

the endothelial NO system and the macula densa NO

system seem to importantly in¯uence volume regula-

tion. Remarkably, the two systems respond in an

opposite fashion to changes in extracellular ¯uid

volume. The endothelial NO system increases its

activity upon increases in perfusion pressure and shear

stress. The endothelial NO system seems an adaptive

mechanism towards increases in perfusion pressure and

high Ang II activity. In contrast, the macula densa NO

system decreases its activity upon the increase in distal

delivery resulting from an increase in ECFV. The

macula densa NO system is regulated by long-term

changes in distal delivery and may well mediate renin

release. These responses lead to adequate vasodilation

and suppression of renin release, enabling restoration

of the ECFV. At present, the detailed responses of the

NOS enzymes in the medulla have not been docu-

mented, however, the available data suggest that the

medullary NO systems participate in pressure natriur-

esis.

Financial support for studies from our laboratory presented in this

paper was provided by grants from the Dutch Kidney Association

(93.1321 and 98.1718).

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II Macula densa NO system

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