factors regulating renal angiotensin-converting enzyme activity in the rat

Factors regulating renal angiotensin-converting enzyme

activity in the rat

V . Z . C . Y E and K . A . D U G G A N

Hypertension Laboratory, South-western Sydney Area Health Service, Australia

ABSTRACT

Changes in angiotensin-converting enzyme (ACE) activity appear to be important in mediating the

natriuresis which ensues after administration of an oral or gastric sodium load. In this study, we

sought to determine the time course of the changes in ACE activity in the kidney which occur after

sodium ingestion. In addition, we sought to investigate mechanisms which might underlie these

changes. Angiotensin-converting enzyme activity was measured by generation of histidyl-leucine in

homogenates of kidneys harvested at varying time-points after gastric sodium administration. The

effects of intravenous sodium loading, solution osmolality and of changes in renal nerve activity were

also investigated. Intragastric instillation of both the sodium-containing solution and its iso-osmotic

urea control solution resulted in significant increases in renal ACE activity (NaCl: P < 0.0005; Urea:

P < 0.01). The increase in renal ACE activity after gastric sodium loading was more prolonged than

after the urea control (P < 0.025, NaCl vs. urea at 90 min). This prolonged increase in renal ACE

activity appeared to re¯ect a response to absorbed sodium as intravenous sodium administration

caused a signi®cant increase in renal ACE activity at 90 min (P < 0.0005). In contrast to these stimuli

which increased renal ACE activity, renal denervation caused a signi®cant decrease in ACE activity in

the kidney (P < 0.05). We conclude that gastric sodium loading increases renal ACE activity. This

effect appears to be due initially to a response to an increase in gastric lumenal osmolality and later to

absorbed sodium. These changes in renal ACE activity are not mediated by a decrease in renal nerve

activity.

Keywords angiotensin-converting enzyme, gastric sodium monitor, renal ACE activity, sodium

loading.

Received 14 June 1999, accepted 14 December 1999

The concept that the gastrointestinal tract participates in

sodium homeostasis was proposed by Lennane et al.

(1975a, b), after studies in man and rabbit demonstrated

a greater and more rapid natriuresis in response to gastric

or oral sodium loading than administering the same

sodium load intravenously. This phenomenon, termed

the gastric sodium monitor, has now been con®rmed to

occur in a number of species (Morita et al. 1993, Mu et al.

1995a, b, Duggan et al. 1996). The gastric sodium

monitor is thought to consist of a sodium sensor located

in the stomach or upper intestine (Cooke 1989), a

mediation system to signal the kidney to increase sodium

excretion and a renal effector system. Although the

intermediary mechanisms whereby the kidney is

signalled to increase urine sodium excretion have been

elucidated (Duggan et al. 1989, 1996, Morita et al. 1993),

the exact nature of the gut sodium sensor and the

intrarenal effector system have not.

Sodium ingestion causes release of the gut-derived

natriuretic peptide vasoactive intestinal peptide (VIP)

into the portal circulation (Duggan et al. 1989). Further,

sodium, unlike other stimuli which release VIP from

the gut into the portal circulation, induces a decrease in

VIP catabolism by both the liver and the lung (Hawley

et al. 1991a, b). This decrease in its catabolism permits

the secreted VIP to reach the kidney and effect a

natriuresis. Simultaneously, with VIP release, there is a

decrease in the circulating concentration of the anti-

natriuretic peptide angiotensin II (Ang II), so that a

sodium-conserving stimulus to the kidney is reduced

(Duggan et al. 1996). This decrease in circulating Ang II

after gastric sodium administration does not result from

a decrease in the concentration of renin (Duggan et al.

1996, Ye & Duggan 1999). Instead, decreases in

angiotensin-converting enzyme (ACE) activity and

angiotensinogen synthesis by the liver appear to

Correspondence: Prof. Karen A. Duggan, Hypertension Service, Bankstown-Lidcombe Hospital, Eldridge Road, Bankstown NSW 2200,

Australia.

Acta Physiol Scand 2000, 169, 21±27

Ó 2000 Scandinavian Physiological Society 21

underlie the decrease in Ang II (Ye & Duggan 1999).

The importance of changes in ACE activity to the

mediation system for the gastric sodium monitor was

demonstrated by Mu et al. (1997). They found that the

greater and more rapid natriuresis, which ensued after

gastric sodium administration, was abolished by prior

treatment with the ACE inhibitor enalapril.

In addition to these humoral components of the

mediation system, changes in hepatic nerve activity and

renal nerve activity have been shown to participate in

the natriuresis (Morita et al. 1993). Hepatic denervation

was found to abolish the natriuresis in response to

gastric sodium, whilst renal denervation was found to

signi®cantly decrease the natriuresis but not to totally

abolish it. Further studies showed that a decrease in

renal nerve activity occurred following gastric sodium

administration. Thus, these studies together suggested

that a decrease in renal nerve activity was integral to the

increase in urinary sodium excretion consequent upon

gastric sodium loading.

As changes in hepatic ACE activity appear import-

ant in the mediation system, we sought in a pilot study

to determine whether changes in renal ACE activity

might also participate in effecting the natriuresis after

gastric sodium loading (Ye & Duggan 1997). That is,

whether changes in renal ACE activity might form part

of the intrarenal effector system for the gastric sodium

monitor. We found that unlike hepatic ACE activity,

which decreased, renal ACE activity increased

following gastric sodium loading. In this study, we

sought therefore to explore the time course of this

increase in renal ACE activity and to determine the

mechanism(s) underlying it. Speci®cally, we sought to

determine whether the osmolality of the sodium-con-

taining solution might underlie this increase in renal

ACE activity, whether absorbed sodium and an

increase in plasma sodium might be responsible, or

whether it was mediated by a decrease in renal nerve

activity.

METHODS

Experimental protocols

Male Sprague±Dawley rats weighing 250±300 g were

placed on a low-sodium diet (0.008%) (Janos. Chem-

icals, Forbes, NSW, Australia) for 7 days. Precondi-

tioning with a low-sodium diet has been found to be

the most effective and reproducible method of

demonstrating activation of the gastric sodium monitor.

That is, demonstrating the greater and more rapid

natriuresis after gastric sodium loading than occurs

after intravenous sodium loading. On the day of

experiment, the rats were randomly allocated to one of

four treatment groups:

(a) Intragastric sodium load 1.5 mmol kg±1 as

0.513 M NaCl solution to de®ne the time course of

the change in renal ACE activity.

(b) Intravenous sodium load 1.5 mmol kg±1 as

0.513 M NaCl solution to determine whether an

increase in plasma sodium might induce the

increase in renal ACE.

(c) Intragastric administration of an iso-osmotic

(5.95%) urea solution to determine the contribution

of the osmolality of the sodium-containing solu-

tion.

(d) Intravenous administration of an iso-osmotic urea

solution to determine the contribution of the

osmolality of the sodium-containing solution to the

changes from intravenous sodium.

(e) Renal denervation to determine whether a decrease

in renal nerve activity might underlie the change.

Hypertonic NaCl solutions and urea were used to

minimize the volume of solution delivered (0.73±

0.88 mL). This was to prevent either gastric distension

or plasma volume expansion acting as stimuli for

changes in ACE activity.

These experiments complied with the Australian

Code of Practice for the Care and Use of Animals for

Scienti®c Purposes (Sixth Edition 1997) and were

approved by the Animal Ethics Committee of the

University of New South Wales.

Gastric sodium administration

The rats were anaesthetized using halothane 2.5%

delivered in nitrous oxide (1 L min±1) and oxygen

(0.5 L min±1) via a non-rebreathing mask. The

abdomen was opened via a mid-line incision through

the linea alba. After a 1-h rest equilibration period, a

sodium load of 1.5 mmol kg±1 as 0.513 M NaCl was

delivered into the gastric lumen by direct puncture

using a 26 gauge needle. The kidneys were harvested at

0, 30, 60 and 90 min after sodium administration

(n � 8 rats at each time-point). Following harvesting,

the kidneys were immediately snap frozen in liquid

nitrogen and stored at ±80 °C until assay.

Intravenous sodium administration

To determine whether an increase in plasma sodium

consequent upon sodium absorption from the intestine

caused the increase in renal ACE activity, the rats were

equilibrated to diet and anaesthetized as above. The

abdomen was entered via an incision through the linea

alba and, after a 1-h rest equilibration period, the saline

load of 1.5 mmol kg±1 as 0.513 M NaCl was given by

iliac vein injection. Kidneys were harvested and snap

frozen as above.

22 Ó 2000 Scandinavian Physiological Society

Regulation of renal ACE � V Z C Ye and K A Duggan Acta Physiol Scand 2000, 169, 21±27

Intragastric osmotic stimulus

To determine whether the change in renal ACE activity

might re¯ect a response to the osmolality of the sodium-

containing solution, we investigated the effect of an iso-

osmotic (5.95%) urea solution. Urea was chosen for

this control because we have shown previously that it

does not affect the humoral mediation system for the

gastric sodium monitor.

Male Sprague±Dawley rats were prepared as above.

After anaesthesia, a mid-line incision was made through

the linea alba. Following a 1-h rest equilibration period,

the 5.95% urea solution was administered by direct

gastric puncture using a 26 gauge needle.

Kidneys (n � 8 rats at each time-point) were

harvested and snap frozen, as described above.

Intravenous osmotic stimulus

To determine whether changes in renal ACE activity

after intravenous sodium loading were a response to the

sodium load per se or to the osmolality of the sodium-

containing solution rats were prepared as in `intragastric

osmotic stimulus'. After a 1-h rest equilibration period,

an equivalent volume of the iso-osmotic urea solution

was given by iliac vein injection. Kidneys were

harvested and snap frozen as above.

Renal denervation

Gastric sodium loading is associated with a decrease in

renal nerve activity and the ensuing natriuresis can be

prevented by renal denervation. To determine whether

the effects of intragastric sodium loading on renal ACE

activity are mediated by changes in renal nerve activity,

we measured renal ACE before and after denervation.

Brie¯y, male Sprague±Dawley rats were equilibrated

to a low-sodium diet for 7 days and then anaesthetized,

as above. The abdomen was entered via a mid-line

incision through the linea alba. The left kidney was

identi®ed and renal capsule removed. The renal vessels

were then stripped and painted with 5% phenol in

dextrose.

The left kidney was harvested before and at 30, 60

and 90 min after denervation. Following harvesting, the

kidneys were immediately snap frozen in liquid nitrogen

and stored at ±80 °C, as above.

Combined effects of denervation and gastric sodium loading

As denervation and gastric sodium loading had

opposing effects on renal ACE activity the effect of

unilateral denervation combined with sodium adminis-

tration were investigated in the left kidney and

compared with that of sodium administration alone in

the right kidney.

Male Sprague±Dawley rats were prepared as above

and the abdomen entered via a mid-line incision

through the linea alba. After a 1-h rest equilibration

period, the left kidney was denervated as above and a

gastric sodium load of 1.5 mmol kg±1 administered.

Both the right and left kidneys were harvested before

denervation and sodium administration (control) and at

30, 60 and 90 min after these manoeuvres. The kidneys

were snap frozen in liquid nitrogen and stored at

±80 °C until assay.

Renal ACE activity

Each kidney was pulverized individually using a stain-

less steel tissue grinder and anvil pre-cooled in liquid

nitrogen. The pulverized tissue was suspended in

20 mL of phosphosaline buffer (0.5 mol L±1 K2HPO4,

1.5 mol L±1 NaCl, pH 8.4) and homogenized using an

Omni 2000 (Omni International, USA) homogenizer at

speed 3 for 60 s. The homogenate was then aliquotted

and stored at ±20 °C until ACE activity was assayed.

To determine ACE activity, duplicate 100-lL

aliquots were incubated with 240-lL hippuryl-histidyl-

leucine (5 mM) for 45 min. The reaction was stopped

by addition of 1.45 mL of 0.28 M NaOH. The histidyl-

leucine generated was estimated ¯uorimetrically

following incubation with 2% o-phthaldialdehyde in

methanol for 10 min (Friedland & Silverstein 1976).

Fluorescence was determined by excitation omission

(350/500 nM) ¯uorimetry using an Hitachi F2000

¯uorimeter. The amount of histidyl-leucine generated

was derived from comparison with a standard curve.

Statistical analysis

Changes in renal ACE activity in each experimental

group with time was assessed using analysis of variance.

When signi®cant differences were found, individual

comparisons were made by t-test using a pooled vari-

ance estimate (CSS-Statistica). Comparisons at each

time-point between different treatment groups were

made by t-test using a pooled variance estimate.

P-values of <0.05 were accepted as signi®cant.

RESULTS

Intragastric sodium loading

After administration of intragastric saline, there was an

increase in renal ACE activity. This was apparent at

30 min after saline administration when ACE activity in

the kidney had increased from 66.5 � 7.6 nmol min±1

(g tissue)±1 in controls to 164.3 � 17.8 nmol min±1


Acta Physiol Scand 2000, 169, 21±27 V Z C Ye and K A Duggan � Regulation of renal ACE

(g tissue)±1 (P < 0.0005). Thereafter, renal ACE activity

continued to increase (see Fig. 1a).

Intravenous sodium loading

Intravenous administration of the saline solution also

caused an increase in ACE activity in the kidney (see

Fig. 1b). However, this increase occurred later than that

observed after intragastric saline and did not become

signi®cant until 90 min after sodium administration.

Renal ACE activity, 90 min after saline administration,

was 114.8 � 5.1 nmol min±1 (g tissue)±1, which was

signi®cantly greater than in controls 76.3 � 2.2 nmol

min±1 (g tissue)±1 (P < 0.0005).

Intragastric osmotic stimulus

Administration of the iso-osmotic urea solution intra-

gastrically also resulted in an increase in renal ACE

activity (see Fig. 1c). This increase was apparent by

30 min when ACE activity was 145.6 � 16.0 nmol

min)1 (g tissue))1, which was signi®cantly greater

than in controls 67.6 � 7.0 nmol min±1 (g tissue)±1

(P < 0.01). A further non-signi®cant increase was

observed at 60 min. Thereafter, ACE activity in the

kidney decreased. Angiotensin-converting enzyme

activity in the kidney, after intragastric urea, was similar

to that after intragastric saline for the ®rst 60 min.

However, at 90 min, renal ACE activity was signi®-

cantly greater following intragastric saline 198.6 �

13.2 nmol min±1 (g tissue)±1 than following intragastric

urea 157.1 � 8.6 nmol min±1 (g tissue)±1 (P < 0.025).

Intravenous iso-osmotic urea

After intravenous administration of the iso-osmotic

urea-containing solution, there was a small non-

signi®cant increase in ACE activity at 30 min [87.2 �

3.9 nmol min±1 (g tissue)±1] and thereafter renal ACE

activity remained stable [60 min: 89.2 � 3.6 nmol

min)1 (g tissue)±1; 90 min: 84.9 � 4.5 nmol min±1

(g tissue)±1 (see Fig. 1d)]. Angiotensin-converting

enzyme activity in the kidney was signi®cantly lower

90 min after intravenous administration of the osmotic

control solution [84.9 � 4.5 nmol min±1 (g tissue)±1]

than when this solution was administered intragastri-

cally (157.1 � 8.6, P < 0.001).

Effect of denervation

Unlike the other three stimuli, renal denervation caused

a decrease in ACE activity in the kidney (see Fig. 2).

This decrease was apparent from 30 min when renal

ACE activity had decreased from 62.5 � 8.2 nmol

min±1 (g tissue)±1 in controls to 41.2 � 3.1 nmol

min)1 (g tissue)±1 (P < 0.05). Thereafter, renal ACE

activity plateaued, remaining signi®cantly lower than

control at 60 min [40.9 � 4.5 nmol min±1 (g tissue)±1,

P < 0.025] and 90 min [38.0 � 1.1 nmol min±1 (g

tissue)±1, P < 0.01].

Figure 1 (a) Renal ACE

activity before and at various

times after administration of

an intragastric sodium load of

1.5 mmol kg±1 as 0.513 M

saline. **P < 0.0005 compared

with control. Values are

mean � SEM for n � 8 rats at

each time-point. (b) Renal

ACE activity before and after

intravenous administration of

the sodium load. **P < 0.0005

compared with control. (c)

Renal ACE activity before and

after intragastric administra-

tion of the osmotic control

solution. *P < 0.01,

**P < 0.0005 compared with

control. (d) Renal ACE activity

before and after intravenous

administration of the osmotic

control area containing solu-

tion. Values are mean � SEM

for n � 8 rats at each time-

point.



Angiotensin-converting enzyme activity in the

kidney was signi®cantly lower at 30, 60 and 90 min

(41.2 � 3.1, 40.9 � 4.5 and 38.0 � 1.1 nmol min)1

g)1, respectively) after denervation than at 30, 60 and

90 min (164.3 � 17.8, 173.5 � 5.2 and 198.6 � 13.2

nmol min±1 g±1, respectively) after administration of

the saline solution intragastrically (P < 0.0005,

P < 0.0005 and P < 0.0005, respectively). The ACE

activity levels after denervation were also signi®cantly

less than those following intragastric administration of

the iso-osmotic urea control solution [30 min: 145.6

� 16.0 nmol min±1 (g tissue)±1, P < 0.0005; 60 min:

182.6 � 12.5 nmol min±1 (g tissue)±1, P < 0.0005; 90

min: 157.1 � 8.6 nmol min±1 (g tissue)±1, P < 0.0005].

Combined effects of denervation and gastric sodium loading

In the right kidney which was subjected to the effects

of gastric sodium loading but not those of denervation

there was a signi®cant increase in renal ACE activity. At

30 min after sodium loading renal ACE activity had

increased to 72.8 � 4.6 nmol min±1 (g tissue)±1 from

the control value of 51.9 � 4.5 nmol min±1 (g tissue)±1

(P < 0.025). Angiotensin-converting enzyme activity in

the right kidney then remained stable (see Fig. 3a) and

signi®cantly greater than control at 60 min (P < 0.025)

and 90 min (P < 0.025).

In the left kidney, which was subjected to the

combined effects of gastric sodium administration and

denervation, a non-signi®cant increase in ACE activity

was observed (see Fig. 3b).

DISCUSSION

This study clearly demonstrates that ACE activity in the

kidney may be regulated by a number of factors.

Ingested sodium and intravenously administered

sodium, as well as changes in osmolality within the

gastric lumen and changes in renal nerve activity, all

appear to in¯uence the level of ACE activity in the

kidney. Although it has been appreciated that both

plasma and intrarenal renin activities are in¯uenced by a

number of these stimuli (Frederiksen et al. 1975,

Keeton & Campbell 1980, Holdaas et al. 1981, Skott

1988, Morita et al. 19931 ), this is the ®rst study which

demonstrates that other enzymes within the renin±

angiotensin system may be similarly regulated.

The initial increase in renal ACE activity following

the administration of the sodium load intragastrically

may re¯ect a response to a change in the osmolality

within the gastric lumen rather than a response to the

sodium content of the solution. Similar changes were

observed after instillation of both the saline solution

and the iso-osmotic urea control solution. However,

the later increases in renal ACE activity, i.e. those

occurring more than 60 min after administration of

the gastric sodium load appear to be a response to

the sodium content of the solution rather than

the osmolality of the sodium-containing solution. Renal

ACE activity was signi®cantly higher at 90 min in the

rats which received the intragastric sodium than those

which had received the intragastric urea solution

suggesting a sodium effect at this time-point.

The later increase in renal ACE activity 90 min after

administration of the sodium load intragastrically may

be a response to sodium which has been absorbed and

Figure 3 (a) Renal ACE activity in the non-denervated right kidney

after gastric sodium loading *P < 0.025 compared with control. (b)

Renal ACE activity in the left kidney after denervation and gastric

sodium loading.

Figure 2 Renal ACE activity before and at various time-points after

acute renal denervation. *P < 0.025, **P < 0.01 vs. control.



incorporated into the body rather than as a result of

stimulation of the putative gastric or upper intestinal

sodium sensor. That the increase in ACE activity in the

kidney at this 90-min time-point is owing to an effect of

absorbed sodium is supported by the change we

observed in response to intravenous sodium. Although

intravenous sodium was associated with an increase in

renal ACE activity, the increase did not occur until

90 min after the sodium was administered. The increase

in ACE activity in the kidney was not a response to the

osmotic load administered. The iso-osmotic urea

control did not elicit any signi®cant change in renal

ACE activity.

In contrast to the increases in renal ACE activity

induced by gastric sodium and urea administration, as

well as that owing to intravenous sodium administra-

tion, acute renal denervation resulted in a decrease in

ACE activity in the kidney. The decrease in ACE

activity in the kidney following denervation is consis-

tent with earlier data, which have demonstrated a

decrease in renin activity after denervation (Keeton &

Campbell 1980, Morita et al. 1993). Thus, it appears that

renal denervation results in down-regulation of two of

the enzymes in the kidney which are responsible for

angiotensin synthesis. However, the effect of denerva-

tion on renal ACE activity which we observed indicates

that a decrease in renal nerve activity is not the means

by which either intragastrically or intravenously

administered sodium signals the kidney to induce a

change in converting enzyme activity. As Morita et al.

(1993) demonstrated that a decrease in renal activity is

integral to the induction of the greater and more rapid

natriuresis after intragastric sodium, this suggests that

the change in ACE activity resulting from gastric

sodium may subserve a function other than mediating

the natriuresis. This hypothesis is supported by our data

on the combined effects of acute renal denervation and

gastric sodium loading. In the non-denervated kidney

ACE activity increased after gastric sodium as previ-

ously, although the increment was less than after gastric

sodium loading without denervation of the other

kidney. This may re¯ect some effect of reno-renal

nerve traf®c (Zanchetti et al. 1984) resulting in changes

in renal nerve activity in the contralateral non-dener-

vated kidney, which are modifying the response in renal

ACE activity to gastric sodium. This is further

suggested by the ACE activity after gastric sodium

loading in the denervated kidney where ACE activity

was unchanged from control. That is, that these two

manoeuvres (gastric sodium loading and renal dener-

vation) affect ACE activity differently and that the

effects of sodium on ACE activity are not mediated via

a decrease in renal nerve activity, but the level of ACE

activity which results from gastric sodium loading may

be modulated by changes in renal nerve activity.

Angiotensin-converting enzyme in the kidney is

present in the glomerulus, the vascular endothelium,

the vascular bundles of the vasa recta and in the brush

border of the proximal tubule (Chai et al. 1986, Schulz

et al. 1988, Morin et al. 1989, Ikemoto et al. 1990). We

measured total renal ACE and our results therefore

may re¯ect changes that occur predominantly in one

rather than in all of these. The role of ACE in the

glomerulus is not de®ned while in vascular structures

its primary function is Ang II synthesis. In the brush

border of the proximal tubule ACE may function as a

non-speci®c peptidase catabolizing peptides and

proteins ®ltered at the glomerulus. The early phase up-

regulation of renal ACE activity appears to have been

engendered by an increase in osmolality within the

gastric lumen. Such a change in gastric lumenal

osmolality would normally be associated with ingestion

of food, and, thus, this initial increase in renal ACE

activity may be in anticipation of a greater ®ltered

protein and peptide load.

We conclude that renal ACE activity is acutely

up-regulated by increases in the osmolality of the gastric

lumen and that this up-regulation is not mediated by a

decrease in renal nerve activity.

We wish to thank the National Health and Medical Research Council

of Australia for their support for this project.

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factors regulating renal angiotensin-converting enzyme activity in the rat

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