ANALYTICAL AND QUANTITATIVE CYTOPATHOLOGY AND HISTOPATHOLOGY

1. 54
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/20/4202-0054/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
OBJECTIVE: To investigate whether paricalcitol could
ameliorate kidney injury due to ischemia reperfusion
(I/R) in an experimental study.
STUDY DESIGN: Rats were divided into 4 groups:
control, paricalcitol, I/R, and paricalcitol+I/R, each con-
taining 7 animals. Intraperitoneal 0.3 μg/kg paricalcitol
was administered to rats once a day for 5 consecutive
days in the paricalcitol and paricalcitol+I/R groups.
After right nephrectomy, rats were exposed to ischemia/
reperfusion on day 6 in the paricalcitol+I/R and I/R
groups. Oxidant and antioxidant parameters, kidney
function tests, and histology were investigated.
RESULTS: Serum urea and creatinine levels exhibited
a significant decrease in rats treated with paricalcitol
before I/R as compared to rats exposed just to I/R. In a
comparison of the paricalcitol+I/R group with the I/R
group, serum total oxidant status (TOS) levels decreased
significantly; serum total antioxidant capacity (TAC)
and nitric oxide levels, however, increased significantly
with paricalcitol administration. Malondialdehyde and
TOS levels of kidney tissue were significantly lower,
whereas TAC and paraoxonase levels were higher in
the paricalcitol+I/R group than in the I/R group. Renal
tissue injury scores were found to be significantly higher
in the I/R group than in the paricalcitol+I/R group.
CONCLUSION: Pretreatment with paricalcitol was
detected to be renoprotective by decreasing renal injury
related with renal I/R, which was assessed by improved
renal function and histopathology. (Anal Quant Cyto-
pathol Histpathol 2020;42:54–60)
Keywords: acute kidney injury; antioxidants; dis­
Pretreatment with Paricalcitol Attenuates
Oxidative Stress in Renal Ischemia
Reperfusion–Induced Nephropathy in Rats
Fatma Yilmaz Aydin, M.D., Zülfükar Yilmaz, M.D., Yasar Yildirim, M.D.,
Emre Aydin, M.D., Aydin Ketani, M.D., Veysi Bahadir, M.D.,
I
·
brahim Kaplan, M.D., and Deniz Yilmaz, M.D.
From the Departments of Internal Medicine, of Nephrology, of General Surgery, of Biochemistry, and of Pathology, Dicle University
Faculty of Medicine; and the Department of Histology and Embryology, Dicle University Faculty of Veterinary Medicine, Diyarbakir,
Turkey.
Fatma Yilmaz Aydin is Assistant Professor, Department of Internal Medicine, Dicle University Faculty of Medicine.
Zülfükar Yilmaz is Associate Professor, Department of Nephrology, Dicle University Faculty of Medicine.
Yasar Yildirim is Associate Professor, Department of Nephrology, Dicle University Faculty of Medicine.
Emre Aydin is Assistant Professor, Department of Nephrology, Dicle University Faculty of Medicine.
Aydin Ketani is Professor, Department of Histology and Embryology, Dicle University Faculty of Veterinary Medicine.
Veysi Bahadir is Associate Professor, Department of General Surgery, Dicle University Faculty of Medicine.
I
·
brahim Kaplan is Assistant Professor, Department of Biochemistry, Dicle University Faculty of Medicine.
Deniz Yilmaz is Assistant Professor, Department of Pathology, Dicle University Faculty of Medicine.
This study was supported by Dicle University Research Foundation (Reference Number: 13-TF-58).
Address correspondence to: Zülfükar Yılmaz, M.D., Department of Nephrology, Dicle University Faculty of Medicine, Fiskaya Street,
Kitilbil District, Sur/Diyarbakir 21280, Turkey (drzulf21@gmail.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. Volume 42, Number 2/April 2020 55
Effects of Paricalcitol on Renal Injury
ease models, animal; ischemia-reperfusion injury;
kidney; oxidative stress; paricalcitol; rats, Sprague-
Dawley; reperfusion injury.
Acute kidney injury is described as a sudden
decline of the kidney functions over a period of
hours to days or weeks, resulting in the accu­
mulation of nitrogenous waste products such as
blood urea nitrogen and creatinine. Acute kidney
injury is prevalent among patients admitted to
hospital, particularly among those patients in the
intensive care unit.1
Several clinical conditions can cause acute kid-
ney injury; among them, renal ischemia/reperfu-
sion (I/R) injury is known to be one of the most
common. Several clinical situations, such as partial
nephrectomy, shock, sepsis, major vascular sur-
gery, kidney transplantation, and certain hypoten­
sive states are common causes of renal reperfu-
sion injury.2 I/R injury may cause delayed graft
function and renal graft rejection during renal
transplantation.3-5
Despite the fact that reperfusion of ischemic
tissue is vitally important for preventing irrever-
sible cellular injury, reperfusion itself may also
cause additional tissue injury, even more than that
generated by ischemia alone.6,7 Oxidative stress
seems to be a prominent cause of renal I/R in­
jury, although the pathogenesis has not been com­
pletely elucidated.6 Reactive oxygen species (ROS)
formed in a high concentration during I/R injury.8
A disequilibrium between ROS generation and re-
moval ability of their toxic effects by our antioxi-
dant capacity causes oxidative stress.9
Novel selective vitamin D receptor agonist pari-
calcitol is commonly used for secondary hyper­
parathyroidism therapy with fewer side effects
on serum calcium and phosphorus.10,11 Beyond its
well known effects on bone mineral metabolism,
paricalcitol has been shown to exert antioxidant
and antiinflammatory effects.12 Numerous studies
have shown that paricalcitol attenuates kidney
injury, proteinuria interstitial fibrosis, and renal
inflammation.13-16
In this study, we examined the efficacy of par-
icalcitol on kidney function disturbances, oxida-
tive stress, and histological damage in renal is-
chemia/reperfusion injury.
Materials and Methods
Animals
Twenty-eight male Sprague-Dawley rats were en-
rolled in this experimental study, each weighing
180–250 g. Rat food as well as water ad libitum
were given to the animals, and they were kept
under standardized conditions. Approval was ob-
tained from the local committee on animal research
ethics of the School of Medicine, Dicle University.
Experimental Protocol and Groups
Twenty-eight rats were assigned to 4 groups, each
containing 7 animals:
• Group 1 (control): Rats in this group received
saline solution 0.9% intraperitoneally once a day
for 5 days (the same as the paricalcitol dose).
Rats in the group were not exposed to ische-
mia/reperfusion (I/R) injury. Blood and kidney
tissue samples were taken after laparotomy on
the sixth day.
• Group 2 (paricalcitol): Intraperitoneal 0.3 μg/kg
paricalcitol was administered to rats once a day
for 5 days. Rats in this group were not exposed
to ischemia/reperfusion (I/R) injury. Blood and
kidney tissue samples were taken after laparo-
tomy on the sixth day.
• Group 3 (ischemia/reperfusion [I/R]): Rats in this
group received saline solution 0.9% intraper­
itoneally once a day for 5 days (same as the
paricalcitol dose). After right nephrectomy, rats
were exposed to ischemia/reperfusion (60 min­
utes left renal artery occlusion, then 60 minutes
reperfusion period) on day 6. Blood and left
kidney tissue samples were taken after 1 hour
of reperfusion period.
• Group 4 (paricalcitol+I/R): Intraperitoneal 0.3 μg/
kg paricalcitol was administered to rats once a
day for 5 days. After right nephrectomy, rats
were exposed to ischemia/reperfusion (60 min­
utes left renal artery occlusion, then 60 minutes
reperfusion period) on the sixth day. Blood
and left kidney tissue samples were taken after
1 hour of reperfusion period.
Xylazine (10 mg/kg) and ketamine (70 mg/kg)
were given to all of the rats for anesthesia by in-
tramuscular route. After antisepsis with povidone-
iodine, the anterior abdominal was opened by
local midline incision. Right nephrectomy was per­
formed and then, with atraumatic vascular clamp
placed on the left renal artery, blood flow was
cut off and a 60-minute ischemia was started.
The clamp was removed after the ischemia stage,
then reperfusion was started (kidney color change
followed up 2 minutes after the clamp was re-

3. 56 Analytical and Quantitative Cytopathology and Histopathology®
Aydin et al
moved). The incision was closed and cleaned with
povidone. Subcutaneous 2 mL saline was given to
correct fluid loss during the surgical operation.
As a result of the ischemia-reperfusion per-
formed, all of the rats were sacrificed through
intracardiac puncture, and the left kidneys were
harvested. Blood samples were centrifuged, and
plasma samples taken were kept at −70°C imme­
diately until assayed. Kidneys were divided into
major structures from the pelvis for histopatholo­
gical evaluation and laboratory analysis (stored at
−70°C until biochemical analysis).
Evaluation of Renal Function
An Aeroset C16000 analyzer (Abbott, Chicago,
Illinois, USA) was used for measurement of serum
urea and creatinine.
Biochemical Analysis
Tissue samples were first homogenized by a ho­
mogenizer after weighing the tissues. Serum and
kidney tissue specimens were examined for oxi­
dant (malondialdehyde, total oxidant status [TOS])
and antioxidant parameters (nitric oxide, para-
oxonase, and total antioxidant capacity [TAC]).
Malondialdehyde was determined with the thio-
barbituric acid method.17 TOS18 and TAC19 were
determined through use of a new measurement
method developed by Erel. Paraoxonase and ni-
tric oxide were measured by employing available
kits.20
Histopathological Evaluation
Histopathological evaluations were performed un-
der a light microscope. The kidneys were fixed in
10% formaldehyde, then inserted to paraffin. Five
μm sample sections were obtained for staining by
using periodic acid–Schiff and hematoxylin and
eosin. The following histological parameters were
examined with respect to morphological kidney
damage: tubular necrosis and atrophy, hydropic
degeneration, regenerative atypia, interstitial fibro-
sis, and loss of brush border.21 The analysis was
performed with the sum of the individual scores
(0 to 3): no findings (0), mild (1), moderate (2), and
severe (3) for kidney.
Statistical Analyses
Statistical Package for the Social Sciences (SPSS),
Version 18.0 for Windows, was employed to per-
form data analyses. All of the data were reported
with mean±standard deviation. One-way analysis
of variance (ANOVA) with a post-hoc Bonferroni
correction was performed for multiple group com-
parison. P<0.05 was considered statistically signi-
ficant.
Results
As compared to control and paricalcitol group
animals, those animals that underwent renal is-
chemia were detected to have significantly higher
serum creatinine and urea levels (p<0.05). Serum
urea and creatinine levels exhibited significant
decrease in rats treated with paricalcitol before
ischemia reperfusion as compared to rats exposed
to ischemia reperfusion alone (p<0.001). Table I
shows the renal function tests of the groups.
In comparing the paricalcitol+I/R group with
the I/R group, we found that serum TOS levels
decreased significantly, whereas serum TAC and
nitric oxide levels increased considerably with
paricalcitol administration. Malondialdehyde and
TOS levels of kidney tissue were significantly
lower, whereas TAC and paraoxonase levels were
detected to be meaningfully higher in the parical­
citol+I/R group with respect to the I/R group.
Table II illustrates the oxidant as well as antioxi-
dant parameters of the study groups.
Table I Effect of Paricalcitol on Renal Function Tests in the Rats According to Group
Group
Control Paricalcitol I/R Paricalcitol+I/R
Parameter (n=7) (n=7) (n=7) (n=7)
Serum
Urea (mg/dL) 28.57±7.80 28.14±4.01 130.60±20.68a,b 75.28±14.02a,b,c
Creatinine (mg/dL) 0.38±0.07 0.36±0.03 1.21±0.21a,b 0.79±0.09a,b,c
ap<0.001 in comparison with the control group.
bp<0.001 in comparison with the paricalcitol group.
cp<0.001 in comparison with the I/R group.

4. Volume 42, Number 2/April 2020 57
Effects of Paricalcitol on Renal Injury
As illustrated in Table III, the renal tissue injury
scores were found to be considerably higher in
the I/R group with respect to the paricalcitol+I/R
group (12.00±1.15 vs. 9.42±0.97, p<0.001). Kidney
light microscopy images of the groups are shown
in Figure 1.
Discussion
Despite advances in critical care medicine, acute
kidney injury is still an important healthcare chal-
lenge throughout the world. The prevalence of
acute kidney injury has increased over the last
decade and is expected to double during the fol-
lowing 10 years.22,23 Moreover, morbidity and mor-
tality of acute kidney injury is observed to have
increased. Ischemia caused by decreased renal per-
fusion is one of the common causes of acute
kidney injury in hospitalized patients. Although
many pharmacological and nonpharmacological
substances against renal I/R injury have been ex-
amined, current treatment for ischemic acute kid-
ney injury is mainly supportive, including renal
replacement therapy. Thus, more convenient and
reliable therapies are necessary.
Paricalcitol is a third generation and selective
vitamin D receptor activator which has also been
shown to have anti-inflammatory and antioxidant
effects. Paricalcitol demonstrated renoprotective
effects in several renal injury models. Park et al
reported that paricalcitol has beneficial effect for
preventing gentamicin-induced renal injury by
ameliorating renal inflammation and fibrosis.24 It
has also been reported that paricalcitol may im-
prove cisplatin-induced renal injury by decreas-
ing the apoptotic, fibrotic, and proliferative fac-
tors.25 In a study conducted by Tanaka et al in a
relatively small number of hemodialysis patients,
the treatment with a vitamin D receptor activa-
Table II Oxidant and Antioxidant Parameters of Serum and Kidney Tissue in the Study Groups
Group
Control Paricalcitol I/R Paricalcitol+I/R
Parameter (n=7) (n=7) (n=7) (n=7)
Serum
MDA (mmol/mL) 4.53±3.35 5.81±3.12 63.83±17.76d,e 48.40±12.05d,e
TOS (µmol/L) 44.33±7.14 99.80±28.24 310.09±106.84d,e
184.24±43.11a,c
TAC (mmol/L) 0.97±0.13 1.07±0.15 1.03±0.17 2.29±0.72a,b,c
NO (µM) 25.60±8.39 21.50±6.41 32.80±10.12 65.01±13.74d,e,f
Paraoxonase (U/L) 86.02±13.22
107.57±50.75
155.10±49.07 204.63±59.41b,d
Kidney tissue
MDA (mmol/mL) 19.91±5.32 29.19±10.99 108.20±25.64d,e 70.44±21.09b,c,d
TOS (µmol/L) 80.43±7.86 100.96±12.22 225.07±64.93d,e 134.30±53.47c,d,e
TAC (mmol/L) 4.96±1.30
4.84±0.74
3.48±0.63 7.43±3.02c
NO (µM) 69.07±11.38 95.77±30.40 146.12±43.28a 213.03±71.64d,e
Paraoxonase (U/L) 54.47±8.97 67.23±10.85 87.44±13.17a 117.76±22.01c,d
MDA = malondialdehyde, NO = nitric oxide, TAC = total antioxidant capacity, TOS = total oxidant status.
ap<0.05 in comparison with the control group.
bp<0.05 in comparison with the paricalcitol group.
cp<0.05 in comparison with the I/R group.
dp<0.001 in comparison with the control group.
ep<0.001 in comparison with the paricalcitol group.
fp<0.001 in comparison with the I/R group.
Table III Renal Histopathological Scores of the Groups
Control Paricalcitol I/R Paricalcitol+I/R
Group (n=7) (n=7) (n=7) (n=7)
Total score Ø Ø
12.00±1.15a,b 9.42±0.97a,b,c
ap<0.001 in comparison with the control group.
bp<0.001 in comparison with the paricalcitol group.
cp<0.001 in comparison with the I/R group.

5. 58 Analytical and Quantitative Cytopathology and Histopathology®
Aydin et al
tor reduced oxidative stress.26 In an experimental
study, Ari et al reported the protective effect of
paricalcitol in contrast-induced nephropathy by de-
creasing the systemic and renal oxidative stress.27
The effectiveness of paricalcitol against ischemia/
reperfusion injury on the kidney was examined by
Hwang et al in mice. They concluded that pretreat-
ment with paricalcitol prevents renal ischemia/
reperfu­sion injury by the inhibition of renal inflam-
mation.28 Recently, Lee et al also demonstrated the
renoprotective effect of paricalcitol in ischemic
acute kidney injury by attenuating inflammation.29
In another experimental study by Azak et al, the
effect of paricalcitol was evaluated on renal I/R
injury.3 Paricalcitol pretreatment showed an im-
provement in terms of oxidant parameters, antiox-
idant parameters, creatinine levels, and in histopa-
thology, suggesting that paricalcitol is efficacious
in terms of preventing renal I/R injury. Com-
patible with the findings of previous works, our
study showed that pretreatment with paricalcitol
attenuated renal I/R injury by indicating a major
reduction in the serum urea and creatinine levels.
I/R injury is defined as cellular damage after
reperfusion of ischemic tissues.6 Although several
factors are associated with renal I/R injury, oxi­
dative stress due to an imbalance between the
oxidative system and the antioxidative defense
system has a substantial role in reperfusion injury
pathogenesis. During ischemia, the catabolic de-
gradation of ATP ensures hypoxanthine. It is
normally oxidized to xanthine with xanthine de-
hydrogenase.6 Together with ischemia, xanthine
dehydrogenase is transformed to xanthine oxi-
dase. On the other hand, xanthine oxidase can-
not transform hypoxanthine to xanthine because
of oxygen required in this process. Oxygen is
reintroduced after restoration of reperfusion, and
accumulated hypoxanthine is transformed by the
xanthine oxidase, resulting in toxic ROS produc-
tion.2,6 Excessive production of ROS which causes
oxidative stress is highly damaging and can also
lead to cellular injury. ROS is counteracted by local
antioxidant enzymes; however, overproduction of
ROS can overwhelm antioxidant defenses during
reperfusion.30 Malondialdehyde is an end product
Figure 1
Kidney histopathological
findings of the study groups
(hematoxylin and eosin
staining, original magnification,
×200). Normal histology in
(A) Group 1 (control),
(B) Group 2 (paricalcitol),
(C) Group 3 (I/R), and
(D) Group 4 (paricalcitol+I/R).

6. Volume 42, Number 2/April 2020 59
Effects of Paricalcitol on Renal Injury
of lipid peroxidation, which has also been seen to
increase in I/R injury.27
Since renal I/R injury is closely concerned with
oxidative stress, we focused on the oxidant and
antioxidant parameters. Our study showed that
paricalcitol pretreatment led to a major decrease
for serum-kidney TOS and kidney malondialde­
hyde levels and a major increase in serum-kidney
TAC, serum nitric oxide levels, and kidney para-
oxonase levels. Consistent with the findings of
Azak et al, our results also demonstrated the
useful effect of paricalcitol as the pretreatment
against oxidative stress in renal I/R injury.
Moreover, our study has also revealed that
paricalcitol pretreatment results not only in im-
proved renal function, but also in histopatholo-
gical findings by exhibiting significantly lower
renal tissue injury scores in the paricalcitol+I/R
group with respect to the I/R group.
In conclusion, our study has shown that prior
treatment with paricalcitol is effective in reduc­
ing renal injury after renal ischemia/reperfusion,
which has been observed by improvement in
renal functions and histopathology. We are of the
opinion that these effects are attributable to the
beneficial effects of paricalcitol against oxidative
stress.
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