THE POSSIBLE PROTECTIVE ROLE OF CANDISARTAN ON
CYCLOSPORINE INDUCED NEPHROTOXICITY IN RATS
By
Hanan T. Emam M.D.1, Abd El Moneim G. Madbouly M.D.2, Abeer A.
Shoman M.D.3 and Noha. I. Hussein M.D3
1
Department of Pharmacology & Therapeutics, 2Department of Forensic & Toxicology and
3
Department of physiology,
Faculty of Medicine, Benha University, Egypt
ABSTRACT
Cyclosporine A (CsA), a fungal undecapeptide, is the most common
immunosuppressive drug used in organ transplantation and autoimmune diseases.
However, nephrotoxicity is the major adverse effect of CsA use. The molecular
mechanisms of CsA nephrotoxicity are not well characterized, but more recent studies
suggest an involvement of angiotensin ll (ANG II) and reactive oxygen species in the
development of cyclosporine nephrotoxicity. This study was thus designed to
investigate the role of angiotensin II type I (AT1) receptor antagonist, candisartan,on
CsA- induced nephrotoxicity. Three groups of rats were employed in this study; group
1 served as control, group 2 rats were treated with CsA (20mg/kg/day
subcutaneously) for 21 days, and group 3 received CsA along with candisartan
(1mg/kg/day perorally) 24 hr before and 21 days concurrently. Renal blood flow
(RBF) was estimated by flowometer. Estimation of plasma renin activity serum
creatinine, blood urea and tissue malondialdehyde content by using colorimetric
methods. Renal tissue specimens were histopatholgically examined by hematoxylin &
eosin staining. CsA administration for 21 days resulted in a marked renal impairment
and significantly decreases (RBF), deranged the renal functions as well as renal
morphology. All these factors were significantly improved by candisartan. These
results clearly demonstrate the pivotal role of (AT1) receptor antagonist candisartan
in CsA- induced nephrotoxicity.
Keywords: Cyclosporine, Nephrotoxicity, Candisartan, Angiotensin, Renin.
1
INTRODUCTION
Due to its potent immunosuppressive effects, cyclosporine (CsA)
has improved allograft survival in organ transplantation and has been
applied increasingly with considerable clinical benefit in the treatment of
autoimmune diseases. Unlike most other immunosuppressive agents,
cyclosporine has no depressant effects on the bone marrow. However, the
therapeutic benefits of cyclosporine have been frequently limited by the
occurrence of acute and chronic nephrotoxicity, which is the most serious
common side effect. Cyclosporine nephrotoxicity therefore remains an
important clinical challenge (1).
It has been suggested that activation of the renin-angiotensin
system is involved in the pathogenesis of CsA-induced nephrotoxicity (2).
Angiotensin receptor blocker (ARB) as Irbisartan is effective in
preventing CsA- induced vascular and renal adverse effects (2).
Candisartan Cilexetil; an inactive ARB prodrug, which hydrolyzed
to active form during absorption from GLT, due to its tight binding to
AT, receptor it has longer activity than other members of ARBs (3).
2
MATERIALS AND METHODS
Animals
Twenty four male adult albino rats of locally breaded strain
weighing between 150-250g at the beginning of the study were used.
They have acclimatized for one week in groups (8/cage) in fully
ventilated room at ordinary room temperature in pharmacology
department, Benha Faculty of Medicine . Rats were allowed to ad libitum,
access to water and balanced diet All experimental protocols were
approved by the committee of Benha University during September 2012.
At the beginning of the experiment they were divided into 3 groups
each contained 8 rats:
* Study groups:
Rats were randomly divided into 3 groups, each of them consisted
of 8 rats.
 Group 1: Control normal rat.
 Group 2: (cyclosporine nephrotoxic group): Rats of this group
received cyclosporine in a dose of 20 mg/kg daily SC for 21
days(4).
 Group 3 (candisartan treated group): Rats of this group given
the same dose of cyclosporine for 21 days along with candisartan
1mg/kg daily orally, 24 hour before and 21 days concurrently with
cyclosporine treatment (4).
All drugs and chemicals were freshly prepared before each
experiment.
All groups were subjected to the following investigation:
1. Renal blood flow (5) by Doppler flow meter.
3
2. Estimation of plasma renin activity (6).
3. Estimation of blood urea (7).
4. Estimation of serum creatinine (8).
5. Estimation of tissue malondialdehyde (MDA)content. (9).
6. Hitopathological studies (4).
At the end of the experiment, rats were anaesthized with urethane
(0.6 ml/100 gm of 25% freshly prepared solution), of about the
abdominal cavity was opened, blood sample
were collected from
abdominal aorta and processed for biochemical measurements.the
kidneys were exposed, removed and divided into 2 parts.one part was
placed in 10% formaline for histopathological examination. The second
part was kept at -70C and used for biochemical measurement of MAD.
Statistical Analysis:
All data were expressed as mean  S.E, data were evaluated by the
one way analysis of variance. Difference between groups were compared
by Student's t-test with P  0.05 selected as the level of statistical
significance (10).
4
RESULTS
Effect of candisartan on cyclosporine induced nephrotoxicity in rats:
a) The effect on RBF:
There was significant (P < 0.05) reduction of RBF from a mean of
9.4  1.13 cm/s in control normal rats to a mean of 4.140.11 cm/s in rats
received cyclosporine only table (1). (Fig. 1, 6, 7).
RBF was significantly increased from a mean of 4.14 0.11cm/s in
cyclosporine treated rats to a mean of 8.02  0.6cm/s in candisartan
treated group. Table (1). (Fig. 1, 7& 8).
b) Plasma renin activity:
The mean value of plasma renin activity in control normal rats was
1.50 0.06 ng/ml/h. In rats received cyclosporine only this value was
significantly elevated (P < 0.05) to reach 4.37 0.08 ng/ml/h. The mean
value of plasma renin activity in candisartan treated group was
insignificantly increased (P 0.05) to 4.58  0.09 ng/ml/h in comparison to
the corresponding value of cyclosporine treated rats, table (1) (Fig. 2).
c) Blood urea level:
The mean value of blood urea level in control normal rats was
20.42.1 mg/dl. In rats received cyclosporine only this value was
signficiantly elevated (P < 0.05) to reach 49.8  4.2 mg/dl. The mean
value of blood urea level in candisartan treated group was significantly
decrease (P < 0.05) to 31.82.2 mg/dl, in comparison to the
corresponding value of cyclosporine treated rats, (Table 1) (Fig. 3).
5
d) Serum creatinine level:
The mean value of serum creatinine level in control normal rats
was 0.500.06 mg/dl. In rats received cyclosporine only this value was
significantly elevated (P < 0.05) to reach 1.38  0.08 mg/dl. The mean
value of serum creatinine level in candisartan treated group was
significantly decreased (P < 0.05) to 0.58  0.06 mg/dl in comparison to
the corresponding value of cyclosporine treated rats, table (1) (Fig. 4).
e) Tissue MDA level;
The mean value of MDA level in control normal rats was7.500.06
µM/g. In rats received cyclosporine only this value was significantly
elevated (P < 0.05) to reach16.38  1.8 µM/g. The mean value of MDA
level in candisartan treated group was significantly decreased (P < 0.05)
to 10.58 1.06 µM/g in comparison to the corresponding value of
cyclosporine treated rats, table (1) (Fig. 5).
f) Histopathological examination:
Renal sections of control group showed normal glomeruli &
tubules and absence of any calcification (Fig. 9).
It was noticed that cyclosporine induced tubular degeneration and
vaculation, hyalinosis of basement membrane of glomeruli and renal
tubules. Also, there was patchy dystrophic calcification at the
corticomedullary junction and in the dilated tubules indicating
nephrocalcinosis (Fig. 10 & 11).
In the candisartan treated rats, the rats, the hyaline degeneration of
tubular and glomeular basement membrane was markedly decreased,
tubular atrophy and vaculation was much less evident. No calcification
6
was found in the renal interstitium or in the tubules with treatment
(Fig. 12 &13).
Table (1): Mean  S.E.M. of RBF cm/s, Plasma renin activity ng/ml/h.
blood urea level, serum creatinine level in mg/dl and tissue MDA level
µM/g. in control group, cyclosporine nephrotoxic group and candisartan
treated group (n = 8).
Groups
Group 1
(control group)
9.40.08
Group 2
(cyclosporine
nephrotoxic group)
4.140.11*
Group 3
Candisartan
treated group
8.020.6**
1.50.06
4.37  0.08*
4.580.09#
20.42.1
49.84.2*
31.82.2**
0.5 0.06
1.38 0.08*
0.58 0.06**
7.50.6
16.381.2*
10.581.06**
Parameters
RBFcm/s
Plasma renin
activity
ng/ml/h.
Blood urea level
mg/dl
Serum creatinine
mg/dl
Tissue MDA level
µM/g.
*: Significant compared to control group.
**: Significant compared to cyclosporine nephrotoxic group.
#: In significant compared to cyclosporine nephrotoxic group.
7
12
10
**
8
Group 1
6
Group 2
Group 3
*
4
2
0
RBF cm/s
Fig. (1): A histogram showing the effect of candisartan treatment on RBFcm/s
compared to cyclosporine nephrotoxic group
5
4.5
*
#
4
3.5
3
Group 1
2.5
Group 2
2
Group 3
1.5
1
0.5
0
Plasma renin activity
Fig. (2): A histogram showing the effect of candisartan treatment on plasma rennin
activity ng/m1/h compared to cyclosporine nephrotoxic group
8
60
*
50
40
**
Group 1
30
Group 2
Group 3
20
10
0
Blood urea level mg/dl
Fig. (3): A histogram showing the effect of candisartan treatment on blood urea level
mg/dl compared to cyclosporine nephrotoxic group
1.6
*
1.4
1.2
1
Group 1
0.8
**
0.6
Group 2
Group 3
0.4
0.2
0
Serum creatinine mg/dl
Fig. (4): A histogram showing the effect of candisartan treatment on serum creatinine
mg/dl compared to cyclosporine nephrotoxic group
9
20
18
*
16
14
**
12
Group 1
10
Group 2
8
Group 3
6
4
2
0
Tissue MDA level
Fig. (5): A histogram showing the effect of candisartan treatment on tissue MDA
level µM/g compared to cyclosporine nephrotoxic group
*significant compared with control normal group.
**significant compared with cyclosporine nephrotoxic group.
# In significant compared to cyclosporine nephrotoxic group.
 10 
Fig. (6): A trace showing RBF in control normal rat.
Fig. (7): A trace showing RBF in cyclosporine nephrotoxic rat.
Fig. (8): A trace showing RBF in candisartan rat.
 11 
Fig. (9): Cut section of rat kidney of control group showing normal glomeruli
and tubules (H& E x100)
 12 
a
b
b
Fig.(10)
a
b
a
b
a
Fig.(11)
Fig. (10&11):Cut section of rat kidney of cyclosporine nephrotoxic group
showing cyclosporine induced changes in the form of tubular
degeneration (a), vaculation and hyalinosis of the glomerular basement
membrane (b) (H& E x40).
 13 
b
a
Fig. (12)
a
b
a
Fig. (13)
Fig. (12&13):Cut section of rat kidney of candisartan treated group showing
restoration of the tubular (a) and glomerular (b) structure to a very
large extent (H & E x 40).
 14 
DISCUSSION
Cyclosporine is established as the immunosuppressant of choice in
human organ transplantation, because it improves graft survival and is not
associated with myelosupression. Unfortunately, CsA can lead to a wide
spectrum of nephrotoxic complications. Both functional and structural
changes in the kidney of transplant patients and experimental animals
have been reported (2).
The data of the present work revealed that daily administration of CsA
20mg/kg/day S.C for 21 day produced significant reduction of renal
blood flow, significant elevation of blood urea and serum creatinine
levels. Histopathological examination of renal sections demonstrated that
CsA produced tubular atrophy of the proximal convoluted tubules,
interstitial fibrosis, hyalinosis of vascular basement membrane and
nephrocalcinosis at the corticomedullary junction and calicified
concretions in the tubules.
These results are in agreement with
(11,12)
. They reported that, CsA
reduce glomerular filtration rate and renal blood flow by causing
vasoconstriction of the glomerular afferent arterioles.
(13)
Reported that cyclosporine decreases renal blood flow by
constricting the afferent arteriole proximal to the glomerulus. Also,
(1)
reported that CsA produced renal vasoconstriction and systemic
hypertension.
Mean while
(14)
, reported that CsA causes a dose related decrease in
renal function in experimental animals. It produced a significant increase
in serum creatinine and blood urea and a significant decrease in creatinine
clearance.
 15 
(1)
Reported that in chronic CsA induced nephrotoxicity, the main
histological findings in the kidney are the vascular lesions in the
endothelium and smooth muscle cells, severe atrophy, vacuolization and
thickening of the basal membrane can be found.
Moreover,
(15)
observed that chronic CsA administration leads to
loss of proximal tubular epithelial cell integrity and tubular atrophy, a
variable interstitial injury with secondary fibrosis.
(16)
Reported that croticomedullary calcification was seen with CsA.
Calcified laminated concretions in tubules and microcalcification of
single tubular cells were also seen with CsA.
(17)
Reported
that
chronic
cyclosporine
nephrotoxicity
is
characterized by interstital fibrosis and afferent arteriolar hyalinosis.
In the present work, it was observed that daily oral administration
of candisartan 24 hour before and 21 days along with CsA significantly
increase renal blood flow, prevented CsA induced elevation in blood urea
and serum creatinine. Histopahtological examination of renal sections of
candisartan treated group revealed marked improvement as no
calcification was detected at all, tubular and hyalinosis of the blood
vessels were much less evident.
These results are in agreement with(4) who reported that candisartan
inhibited the increase in blood urea and serum creatinine induced by CsA.
(18)
Concluded that candesartan cilexetil can effectively control
hypertension and proteinuria without deterioration in renal allograft
function. These data suggest that treatment with candesartan cilexetil may
be useful for maintaining long-term renal allograft function.
 16 
(19)
Reported that up regulation of vascular endothelial growth
factor seem to be related up regulation of angiotensin II in cyclosporine
nephrotoxicity.
When renal blood flow is substantially reduced, angiotensin II
contributes to the maintenance of glomerular filtration rate by
constricting the efferent glomerular arterioles. In such condition, dilation
of the efferent arterioles by inhibitors of the renin- angiotensin system
may potentiate the reduction in glomerular filtration rate.
Captopril and saralasin have previously been shown to increase
glomerular filtration rate and renal blood flow in CsA treated
normotensive rats(20). Enalapril was also able to prevent the CsA- induced
decline in glomerular filtration rate in diabetic patients (21).
The exact mechanism of CsA-induced nephrotoxicity are not
known, but there are several lines of evidence suggesting an involvement
of the renin- angiotensin system
(4)
. This is also supported by our study
through the finding that plasma renin activity was higher in the CsAtreated than in the control group. CsA has been reported to stimulate
renin production and release in isolated juxtaglomerular cells (22). An
increase in plasma renin activity has been demonstrated in CsA-Treated
rats either on sodium depletion
(3)
, on standard chow
(23)
, or during high
intake of sodium (24,25).
CsA has also been reported to elevate plasma angiotensin II
levels(26). Furthermore,long- term treatment with CsA upregulates AT1
receptors in vascular and renal tissue
(27)
effect of angiotensin II(28,29).
 17 
and increases vasoconstrictive
Chronic administration of angiotensin II in rats produces renal
injury similar to that observed in CsA nephropathy (30,31) Both angiotensin
II and CsA cause an overexpression of transforming growth factor (TGF1), a cytokine which has been implicated in the pathophysiology of
many fibrotic diseases of the kidney and other organs
(31,32)
. In addition,
tubulointerstitial expression of osteopontin, an adhesion molecule
associated with renal fibrosis, is increased by both angiotensin II
(30)
and
CsA(32). Thus, activation of the renin- angiotensin system by CsA may be
at least partly responsible for the interstitial fibrosis through stimulation
of TGF-1 and osteopontin expression. This is also supported by the
finding that the AT1 receptor antagonist losartan reduced the CsAinduced interstitial fibrosis concomitantly with decreased renal TGF-1
and betaig-h3 expression (15).
(19)
Reported that the increased VEGF expression in chronic CsA
nephrotoxicity seems to be related to up-regulation of Ang II. In addition,
VEGF probably exerted its effect via the KDR/FLK-1 receptor, the
actions of VEGF in this model remain speculative, but may be related to
its effect on macrophage infiltration or matrix deposition.
The role of reactive oxygen species formation in the CsA induced
impairment of renal function has been suggested by(33).
(16)
Observed that
oxygen free radicals are one of different mediators for CsA induced
nephrotoxicity. There was increasd production of the lipid peroxidation
product malondialdhyde (MDA) with CsA indicating the oxidative stress
associated with CsA nephrotoxicity.
(34)
Reported that melatonin, through
its antioxidant properties, significantly antagonized CsA induced renal
impairment.
 18 
(35)
Showed that curcumin attenuates cyclosprine induced renal
dysfunction and oxidative stress in rat kidneys through its antioxidant
properties.
(2)
Observed that ANG II induce oxidative strees in vitro and in vivo
and demonstrated the pivotal role of AT1 receptor bloker (irbisartan) in
amelioration of cyclosprine nephrotoxicty through
its antioxidant
properties.
Thus, it is suggested that candisartan produces nephroprotective
effect in the rat model of CsA induced nephrotoxicity. This
nephroprotection of candisartan is based on a combination of angiotensin
receptor antagonism, improvement of endothelial dysfunction and potent
antioxidant properties.
ACKNOWLEDGMENT
Our deep gratitude and appreciation to Dr. Ghada Ahmed Abd El
Fattah Lecturer of pathology, Faculty of Medicine, Benha University for
her
great
help
and
valuable constructive cooperation
histospathological part.
 19 
in
the
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