Antihypertensive effect of interleukin-2 in salt-sensitive Dahl rats.
T Ishimitsu, Y Uehara, A Numabe, H Tsukada, Y Ogawa and S Yagi
Hypertension. 1994;23:68-73
doi: 10.1161/01.HYP.23.1.68
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68
Antihypertensive Effect of Interleukin-2 in
Salt-Sensitive Dahl Rats
Toshihiko Ishimitsu, Yoshio Uehara, Atsushi Numabe, Hiroki Tsukada,
Yoshiichi Ogawa, Shigeru Yagi
Abstract We investigated the effects of interleukin-2, which
stimulates the proliferation and maturation of thymus-derived
lymphocytes, on hypertension and organ injuries in genetically
hypertensive rats. Interleukin-2 (5x10* U/kg body wt) was
subcutaneously injected into Dahl salt-sensitive rats fed a 4%
NaG diet and spontaneously hypertensive rats once a week for
10 weeks. The effects on blood pressure, cardiovascular hypertrophy, and renal function were evaluated. Interleukin-2 treatment lowered blood pressure in Dahl salt-sensitive rats (162
versus 187 mm Hg, P<.005). This antihypertensive effect was
associated with an increase in glomerular filtration rate (589
versus 428 mL/d per 100 g body weight, P<.005) and reduction
in cardiac weight (268 versus 305 mg/100 g body weight,
P<.05). Interleukin-2 also alleviated the marked glomerular
sclerosis in Dahl salt-sensitive rats (glomerular injury score,
151 versus 220; P<.001). In contrast, interleukin-2 did not
affect the development of hypertension or organ injuries in
spontaneously hypertensive rats. Histologically, glomerular
and arterial lesions of the kidney were much less marked in
spontaneously hypertensive rats than in Dahl salt-sensitive
rats. These data indicate that interleukin-2 ameliorates the
development of hypertension and cardiac and renal injuries in
Dahl salt-sensitive rats. (Hypertension. 1994^3:68-73.)
Key Words • interleukin-2 • glomerular filtration rate •
hypertension, sodium-dependent • rats, inbred strains •
heart hypertrophy
ince White and Grollman1 reported the implications of autoimmunity in hypertension after a
renal infarct, an increasing amount of evidence
has been accumulated suggesting an association between hypertension and immune dysfunction in both
humans and experimental hypertensive animals.23 Especially in the case of genetic hypertension, it has been
suggested that the suppressor thymus-derived (T) lymphocyte dysfunctions and subsequent autoimmunities
would bring about vascular injuries and renal damage,
both of which are supposed to contribute to the development and maintenance of hypertension.4"6 In fact, it
has been demonstrated that the periarterial spaces are
infiltrated with inflammatory cells in aged spontaneously hypertensive rats (SHR) and these lesions are
resolved by immunosuppressive therapy.7 Moreover, the
arterial damage in salt-induced hypertension could not
be produced in nude mice.8 More recently, the antihypertensive effects of cytokines, humoral immunomediators produced by immunocompetent cells, were examined in several studies; however, the results were
conflicting.913 This controversy may be derived from the
differences in cytokines and hypertensive animal models
used in the studies.
With regard to hypertensive animal models, most of
the earlier studies have been performed using SHR or
rat models for secondary hypertension. Little data are
available as to the role of the immune system in Dahl
salt-sensitive (Dahl S) rats, a genetic model for saltinduced hypertension. It has been reported that Dahl S
rats are more vulnerable to vascular injuries, eg, intimal
and medial thickening and thrombotic formation with
periarterial infiltration of inflammatory cells, and renal
damage. 14 - 16 These pathophysiological properties
strongly suggest the role of the immune system in the
genesis of hypertension in Dahl S rats.
In the present study, we examined the effects of
interleukin-2 on the development of hypertension and
organ injuries in two genetically hypertensive rat models, Dahl S rats and SHR. Interleukin-2 is a potent
immunomediator and is known to promote proliferation
and maturation of T lymphocytes.17
S
Received January 29,1993; accepted in revised form September
22, 1993.
From the Department of Medicine, Division of Hypertension
and Cardiorenal Disease, Dokkyo University School of Medicine,
Mibu, Tochigi (T.I., A.N., H.T., Y.O., S.Y.), and the Second
Department of Medicine, University of Tokyo (Y.U.) (Japan).
Correspondence to Toshihiko Ishimitsu, MD, Department of
Medicine, Division of Hypertension and Cardiorenal Disease,
Dokkyo University School of Medicine, Mibu, Tochigi 321-02,
Japan.
Methods
All procedures were in accordance with the institutional
guidelines for animal research. Male 6-week-old Dahl S
(n = 10) and Dahl salt-resistant (Dahl R, n=10) rats were
originally obtained from Brookhaven National Laboratories,
Upton, NY, and bred by Eisai Co, Ltd, Tokyo, Japan. The rats
were fed a high salt diet containing 4% NaG (wt/wt). Five
Dahl S and five Dahl R rats were subcutaneously injected with
5x10* U/kg body wt recombinant human interleukin-2 (Toray
Industries, Kanagawa, Japan) dissolved in 100 /xL isotonic
saline once a week; the other rats were injected with 100 yiL
isotonic saline alone following the same procedure. The human interleukin-2 was produced in yeast and purified by liquid
chromatography. Its purity was more than 95%, and its specific
activity was 2.6x10* U/mg protein. The first interleukin-2
injection was given at the same time as the start of the high salt
diet. Systolic blood pressure was measured by the tail-cuff
method every week around 2 PM before interleukin-2 was
injected. After 4, 7, 8, 9, and 10 weeks, a 24-hour urine sample
was collected, and then the rats were killed under pentobarbital anesthesia (30 mg/kg body wt IP). Blood samples were
drawn from the inferior vena cava. The wet tissue weights of
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Ishimitsu et al Interleukin and Dahl Rats
ixv
69
£*. ' ~ *
FIG 1. Ught micrographs show
representative glomeruli assigned
to various severity scores, a: Gkxnerulus showing normal appearance (score 0, from untreated Dahl
salt-resistant rats); b through e: glomeruli showing 0% to 25% (score
1, from treated Dahl salt-sensitive
[S] rats), 25% to 50% (score 2, from
treated Dahl S rats), 50% to 75%
(score 3, from untreated Dahl S
rate), and 75% to 100% (score 4,
from untreated Dahl S rats) sclerosis, respectively; f: glomerulus
showing global sclerosis (score 4,
from untreated Dahl S rats). (Periodic actd-Schlff stain, x300.)
C
the heart and descending thoracic aorta were measured. The
kidney was obtained for histological investigation.
The kidney was fixed with 10% Formalin solution, embedded in paraffin, and 2-jim sections were stained with hematoxylin and eosin and periodic acid-Schiff. Histological evaluation of the kidney was performed by one of the authors
(Y.U.) in a blind fashion. The glomerular and arterial lesions
were evaluated by light microscopy using semiquantitative
scoring methods.15 Briefly, lesion severity was graded from 0 to
4 for glomeruli and 0 to 3 for intrarenal arteries, and the injury
score was calculated by summing the products of the severity
score and the percentage of glomeruli or arteries displaying
the same degree of severity. Figs 1 and 2 show representative
micrographs of glomeruli and intrarenal arteries assigned to
each severity score.
Urinary protein concentration was measured using a protein
assay kit (Bio-Rad Laboratories, Richmond, Calif). The activity of 7V-acetyl-0-D-glucosaniinidase (NAG) in the urine, as an
indicator of tubular injury, was measured using sodio-mcresol-sulphonphthaleinyl Af-acetyl-zS-D-glucosaminide as its
substrate (NAG assay kit, Shionogi Pharmaceutical Co, Osaka,
Japan). Urinary and plasma levels of creatinine were measured with a creatinine autoanalyzer (Beckman Instruments
Japan, Tokyo, Japan).
Male 6-week-old SHR (n=20) and normotensive control
Wistar-Kyoto (WKY) rats (n=14) from the Tokyo University
breeding colony were fed a regular laboratory chow, and
interleukin-2 (5 x 104 U/kg body wt) was administered in the
same manner as in the Dahl rat experiment. After 10 weeks,
rats were killed and examined in the same procedure described in the Dahl rat study.
For evaluation of the effect of interleukin-2 treatment on
blood pressure by direct measurement, 16 male Dahl S rats
aged 6 weeks were fed a high NaCl (4%) diet and treated with
KS^
interleukin-2 (n=8) or vehicle (n=8) for 10 weeks in the same
manner. Then, mean arterial pressure was directly measured
through a PE-50 polyethylene catheter inserted into the
femoral artery with rats under light ether anesthesia using a
pressure transducer coupled to a recorder (AP-600G and
WS-682G, Nihon Kohden, Tokyo, Japan). Blood pressure
values were read when the rats were quiet but responded to a
pinch with forceps.
Values are expressed as mean±SEM. Changes in body
weight and blood pressure were analyzed by analysis of
variance for repeated measures followed by the Bonferroni
method. The two-tailed Student's t test was used for the
comparison of treated with untreated groups. A value of P< .05
was considered significant.
Results
Fig 3 illustrates alterations in systolic blood pressure
over the therapeutic period caused by interleukin-2 in
Dahl rats. Development of hypertension was significantly tempered in Dahl S rats treated with interleukin-2 compared with the untreated group (F=5.08,
P<.04), and the difference was statistically significant
after 7 weeks and thereafter. Directly measured mean
arterial pressure after 10 weeks was also significantly
lower in eight treated Dahl S rats than in eight untreated Dahl S rats (152±2 versus 163±3 mm Hg,
P<.03). Interleukin-2 did not influence blood pressure
in normotensive Dahl R rats. In contrast to the Dahl S
rats, as shown in Fig 4, the development of spontaneous
hypertension in SHR was not influenced by the same
dose (5x10* U/kg body wt) of interleukin-2 (185±2
mm Hg for untreated SHR versus 186 ±3 mm Hg for
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70
Hypertension
Vol 23, No 1 January 1994
Fra 2. Light micrographs show representative intrarenal arteries assigned to various severity scores, a: Artery showing normal
appearance (score 0, from untreated Dahl salt-resistant rats); b: artery showing mild thickening of the intima (score 1, from treated Dahl
salt-sensitive [S] rats); c: artery showing moderate thickening of the intima and hyperplasia and hypertrophy of the media (score 2, from
untreated Dahl S rats); d: artery showing marked thickening of the Intima and media (score 3, from untreated Dahl S rats). (Periodic
acid-Schlff stain, x380.)
treated SHR at the 10th week of the therapeutic
period).
Table 1 summarizes the results of various measurements at the end of the therapeutic period in Dahl rats.
Body weights and urine volumes at the end of the
therapeutic period were similar in the four groups, Dahl
R and S rats with or without interleukin-2 treatment.
Urinary excretions of protein and NAG were greater in
the untreated Dahl S rats than in the untreated Dahl R
rats. However, these parameters were not significantly
0 1
2
3
4
5
6
7
8
0
changed by interleukin-2 treatment when compared
with the untreated control group. Urinary protein excretion also did not differ significantly between the
treated and untreated Dahl S rats at 4, 7, 8, or 9 weeks
(4 weeks, 23±4 versus 22±2 mg/d per 100 g body
weight; 7 weeks, 30±3 versus 32±2; 8 weeks, 31 ±3
versus 29±2; 9 weeks, 32±2 versus 34±2). With regard
to renal function, interleukin-2 improved the decreased
creatinine clearance rate in Dahl S rats. Cardiac ventricles were heavier in untreated Dahl S rats than in
treated Dahl S rats. Interleukin-2 treatment reduced
10
Experimental Period (Week)
Fra 3. Line graph shows effects of interleukln-2 treatment on
time-course changes in systolic blood pressure in Dahl rats. •
indicates treated Dahl salt-sensitive rats; a, untreated Dahl
salt-sensitive rats; • , treated Dahl salt-resistant rats; and o,
untreated Dahl salt-resistant rats. *P<.05, **P<.Q1 vs untreated
group.
0 1
2
3
4
5
6
7
8
9
10
Experimental Period (Week)
FIG 4. Une graph shows effects of interleukln-2 treatment on
time-course changes in systolic blood pressure in spontaneously hypertensive rats (SHR) and Wlstar-Kyoto (WKY) rats. •
Indicates treated SHR; o, untreated SHR; • , treated WKY rats;
and o, untreated WKY rats.
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Ishimitsu et al Interleokin and Dahl Rats
TABLE 1.
Alterations
71
of Various Parameters by Interieukln -2 Treatment In Dahl Rats
Dahl R Rats
Dahl S Rats
Measurement
IL-2
Control
IL-2
Control
Body weight, g
376±14
378±18
381 i 9
380±4
Systolic blood pressure, mm Hg
162±3*
187±5t
121 i 3
121±1
Urine volume, (mL/d)/100 g BW
7.9±1.6
7.1±1.2
1.3
1
8.8±1.0
9±2
Urinary protein excretion, (mg/d)/100 g BW
36±6
35±6*
Urinary NAG excretion, (mU/d)/100 g BW
92±9
110±5§
Plasma creatinine concentration, jtmol/L
26±1
26±1
28 i 2
26±1
Creatinine clearance, (mL/d)/100 g BW
589 ±27*
584±32
Cardiac weight, mg/100 g BW
268±9||
428±29t
305±14±
554 d 20
213d 12
204±16
23.1 ±0.5
23.5±0.71
18.9d 0.7
18.5±0.4
2
Aortic weight, mg/cm
68±13
71J 12
Dahl S indicates Dahl salt-sensitive rats; Dahl R, Dahl salt-resistant rats; IL-2, interieukin-2; BW, body weight; and NAG,
N-acetyl-0-D-glucosaminidase. Values are mean±SEM.
||P<.05, *P<.005 vs respective control values In untreated Dahl S rats.
§P<.05, tP<.01, $P<.005, ^P<.001 vs control values in untreated Dahl R rats.
this hypertensive cardiac hypertrophy by 12%. The
weight of the thoracic aorta per unit area was also
greater in Dahl S rats than in Dahl R rats. However, this
parameter of vascular wall thickening was not significantly reduced by interleukin-2 treatment.
On the other hand, as indicated in Table 2, SHR also
showed cardiovascular hypertrophy at the end of the
experimental period compared with control WKY rats.
However, the renal injury parameters were not significantly different between SHR and WKY rats. Interleukin-2 treatment did not affect blood pressure or cardiovascular and renal injury parameters in SHR.
Table 3 lists the results of histological evaluation of
the kidney in each rat group. After 10 weeks of a high
salt diet, control Dahl S rats demonstrated marked
glomerular sclerosis and arterial lesions compared with
control Dahl R rats. Interleukin-2 treatment brought
about highly significant alleviation of this glomerular
sclerosis in Dahl S rats, although the extent of arterial
lesions was not significantly changed. Control SHR also
showed significantly higher glomerular and arterial injury scores than the control WKY rats; however, the
TABLE 2.
Alterations
Wlstar-Kyoto Rats
injuries were very mild compared with those in Dahl S
rats. Interleukin-2 treatment also tempered this mild
glomerular sclerosis in SHR.
Discussion
In the present study, weekly administration of interleukin-2 attenuated the progression of hypertension in
Dahl S rats. This was accompanied by improvements in
cardiac hypertrophy and renal dysfunction. The reduction of cardiac weight seems to provide evidence for the
antihypertensive effect of interleukin-2 in Dahl S rats.
The alleviation of histological injury of the kidney by
interleukin-2 was not marked; however, it seems significant enough to improve creatinine clearance.
The Dahl S rats treated with interleukin-2 showed
blood pressure 25 mm Hg lower than the untreated
group when evaluated by the tail-cuff method. However,
the blood pressure reduction in Dahl S rats by the same
interleukin-2 treatment was no more than 11 mm Hg in
the second experiment in which arterial pressure was
measured directly. This variation is thought to be derived from the different conditions under which blood
of Various Parameters by lnterieukln-2 Treatment In Spontaneously Hypertensive Rats and
SHR
WKY
IL-2
Measurement
IL-2
Body weight, g
285±6
276±7
290±6
Systolic blood pressure, mm Hg
186±3
185±2*
133±2
134±2
Urine volume, (ml_/d)/100 g BW
11.3±1.2
13.5±1.3
13.8±1.1
13.5±1.6
Control
Control
275 ±8
Urinary protein excretion, (mg/d)/100 g BW
14±1
17±2
14±1
15±1
Urinary NAG excretion, (mU/d)/100 g BW
98±17
89±19
90±20
82±18
Plasma creatinine concentration, /imol/L
26±1
27±1
27±2
28±3
Creatinine clearance, (ml_/d)/100 g BW
500±57
482±65
533±78
530±79
Cardiac weight, mg/100 g BW
278 ±7
275 ±8t
238±6
237±9
Aortic weight, mg/cm2
20.1 ±0.4
19.9±0.5±
17.9±0.6
17.7±0.3
SHR indicates spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; IL-2, interleukin-2; BW, body weight; and NAG, N-acetyl-/5D-glucosamlnidase. Values are mean±SEM.
tP<-01, tP<.005, *P<.001 vs control values In untreated WKY rats.
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72
Hypertension
Vol 23, No 1 January 1994
TABLE 3. Effects of lnterieukln-2 Treatment on
Histotogical Injury Scores of Glomerull and Intrarenal
Arteries In Genetically Hypertensive Rats
Rat Group
Glomerular Injury
Score (0 to 400)
Arterial Injury
Score (0 to 300)
Dahl salt-sensitive
lnterleukin-2
151 ± 9 *
65±7
Control
220±5t
65±m
lnterleukin-2
49±5
6±4
Control
60±4
18±7
lnterieukln-2
48±5§
9±3
Control
71 ± 8 *
14±3||
Dahl salt-resistant
SHR
WKY
lnterleukln-2
38±1
2±2
Control
41 ± 4
6±2
SHR Indicates spontaneously hypertensive rats; WKY, WlstarKyoto rats. Values are mean±SEM.
§P<.05, *P<.001 vs respective control values in untreated
rats.
||P<.05, t f < . 0 1 , tP<-001 vs values in untreated normotensive
control rats.
pressure was measured. In measurements by the tailcuff method, rats were restrained and warmed in a
conscious state, and the value reflects systolic blood
pressure. On the other hand, in the latter experiment,
mean arterial pressure was recorded through a catheter
inserted into the femoral artery with rats under light
ether anesthesia. Moreover, systolic blood pressure
values measured by the tail-cuff method at 10 weeks in
the second experiment were comparable (167±4 versus
190±3 mm Hg for treated versus untreated, P<.005, a
difference of 23 mm Hg). Thus, it is supposed that the
repeated experiment showed a similar degree of antihypertensive effect by interleukin-2 treatment in Dahl S
rats.
Recently, Given et al12 have reported that interleukin-2 did not alter the blood pressure of Dahl S rats.
This seems to conflict with the results of our study, but
several reasons can be offered to explain this discrepancy. First, Given et al gave 5 x 103 U of interleukin-2
per kilogram of body weight to the rats at the beginning
of the experiment and the sixth week and observed the
effects until the eighth week. We gave a dose 10 times
higher every week for 10 weeks. This difference in the
dose and frequency of interleukin-2 injection may be
responsible for the lack of significant antihypertensive
effect in the study of Given et al. Second, the number of
rats used in the experiment was smaller in their study
than in ours. Considering that the antihypertensive
effect of interleukin-2 was modest in our study, the
number of rats might not be large enough to show a
significant blood pressure change in the study of Given
et al. Third, they did not refer to the age of their Dahl
S rats, and effects of interleukin-2 may be influenced by
the age of the rats used.
On the other hand, interleukin-2 did not affect the
blood pressure of the SHR in our study. Tuttle and
Boppana9 have reported that a single subcutaneous
injection of 5 x 103 U/kg interleukin-2 completely abolished the development of hypertension in SHR. However, the result could not be reproduced by other
investigators.10'11 In the present study, although we gave
a 10 times higher dose repeatedly, the development and
progression of hypertension in SHR was not influenced.
Thus, our results add a negative view as to the antihypertensive effect of interleukin-2 in SHR.
In the current study, interleukin-2 attenuated hypertension development in Dahl S rats but failed to affect
hypertension in SHR. Thus, the antihypertensive effects
of interleukin-2 were not constant between the two
genetic models of hypertension. Dahl S rats are known
to develop vasculitis-like arterial lesions, eg, intimal and
medial hyperplasia and thrombotic formation with periarterial massive infiltration of inflammatory cells, in the
kidney and mesentery after a few months of a high salt
diet. 1416 Such histological findings suggest the involvement of an immunological mechanism in the development of hypertension and organ injuries in Dahl S rats,
although the immune system of Dahl rats has been
investigated rarely. On the other hand, in SHR, such
vasculitis-like lesions do not occur until a much later
stage, at a year or later.18 In the current study, parameters of renal function did not differ between SHR and
WKY rats, whereas Dahl S rats showed reduced renal
function. Histological examination also showed much
milder glomerular and arterial lesions in SHR than in
Dahl S rats. Therefore, it is speculated that interleukin-2 is likely to exhibit an antihypertensive effect when
immunologically evoked organ injuries are marked.
Interleukin-2 is supposed to stimulate proliferation
and maturation of T lymphocytes and make up for the
decreased T lymphocyte function in genetically hypertensive rats. Assuming that an autoimmune mechanism
is involved to some extent in the formation of arterial
lesions in hypertensive rats, restoration of the suppressor T lymphocyte function by interleukin-2 treatment
would be expected to reduce such vascular injuries and
thereby may lower the blood pressure. The improvement of renal function by interleukin-2 may have been
brought about by participation of the same mechanism
in the kidney.
In summary, we demonstrated that interleukin-2
treatment attenuated the development of hypertension
as well as reduced cardiac hypertrophy and improved
renal dysfunction in Dahl S rats. However, interleukin-2
did not demonstrate an antihypertensive effect in SHR.
Acknowledgments
We thank Dr Junichi Iwai, Brookhaven National Laboratory, Upton, NY, for supplying Dahl rats. We also thank Dr
Toshio Ikeda, Department of Nephrology, Kanto-Teisin Hospital, Tokyo, Japan, for providing SHR and WKY rats. In
addition, we thank Ms Noriko Ooshima for preparing and
staining tissue sections for histological investigation.
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