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\title{Ranolazine reduces oxidative damage and improves kidney function in
cisplatin-induced nephrotoxicity}



\author[1]{Hatice Goncu}%
\author[1]{Lokman Hekim Tanriverdi}%
\author[1]{Mehmet Gunata}%
\author[1]{Ali Beytur}%
\author[1]{Nigar Vardi}%
\author[1]{Yilmaz Cigremis}%
\author[1]{Hakan Parlakpinar}%
\affil[1]{Inonu Universitesi Karaciger Nakli Enstitusu}%


\vspace{-1em}



  
  \date{May 07, 2026}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Cisplatin (CIS)-induced nephrotoxicity is associated with oxidative
stress, apoptosis, inflammation, and fibrogenesis. In this study, we
investigated the therapeutic effects of ranolazine (RAN), a current
antianginal drug known to experimentally reduce oxidative damage in
CIS-induced nephrotoxicity. We randomly assigned thirty-two Sprague
Dawley rats to one of four groups (Control, CIS, CIS+RAN, and RAN+CIS).
We evaluated kidney function parameters including blood urea nitrogen
(BUN), creatinine (Cre), electrolytes, and albumin, as well as tissue
biochemical parameters including malondialdehyde (MDA) and antioxidant
enzymes. Histopathological parameters were also assessed. We observed a
significant increase in BUN and Cre values in the CIS group compared to
the control group (p\textless{}0.05). However, there was a significant
decrease in BUN values (p\textless{}0.05) in the CIS+RAN and RAN+CIS
groups compared to the CIS group. In contrast, the decrease in Cre
values did not reach statistical significance (p\textgreater{}0.05), and
serum electrolytes were comparable among groups. Furthermore, a
statistically significant increase in albumin levels was observed in the
CIS+RAN group compared to the CIS group (p\textless{}0.05). MDA levels
were significantly decreased in the CIS+RAN group compared to the CIS
group, indicating the antioxidant activity of RAN (p\textless{}0.05).
Histopathological analysis revealed that necrosis and dilatation in
epithelial cells of cortical and medullary tubules were more prominent
in the CIS group (p\textless{}0.0001). However, in the RAN+CIS group,
the histopathological changes observed in the CIS group were found to be
significantly reduced (p\textless{}0.0001). Degenerative changes in
tubules were observed in the CIS+RAN group (p\textgreater{}0.05). Our
findings suggest that the beneficial effects of RAN on CIS-induced
nephrotoxicity may be related to its antioxidant activity.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Cisplatin (CIS) is an antineoplastic agent used to treat various types
of cancer, including testicular, ovarian, bladder, and lung cancer
{[}1{]}. However, its use is limited due to its cumulative and
dose-dependent toxic effects, such as nephrotoxicity, neurotoxicity, and
ototoxicity {[}2{]}. CIS is known to accumulate significantly in the
kidneys, particularly in the proximal tubules, with the S3 segment being
the most affected {[}3{]}. The cellular pathology of nephrotoxicity is
mediated by oxidative stress, apoptosis, inflammation, and fibrogenesis
{[}4{]}. CIS-mediated oxidative stress in renal tubules is initiated by
reactive oxygen species (ROS) and intracellular
Ca\textsuperscript{2+}elevation {[}5{]}.

Ranolazine (RAN) is an antianginal drug that has been studied for
several purposes {[}6{]}. RAN prevents the increase in
Na\textsuperscript{+} by blocking late Na\textsuperscript{+} channels
and the accumulation of cellular Ca\textsuperscript{2+} through
Na/Ca\textsuperscript{2+} exchange (NCX) and restores mitochondrial
function, thereby exerting an antioxidant effect by preventing the
formation of ROS {[}7, 8{]}. It has been shown that oxidative stress
triggers the late Na+ channel, and the accumulation of Na+ and Ca2+ is
the main mechanism in organ damage {[}9{]}. Thus, RAN can counteract the
harmful effects of oxidative stress {[}10{]}.

Currently, preventive strategies, such as monitoring kidney function
before starting nephrotoxic drugs, close patient follow-up, and fluid
administration, are recommended to prevent CIS-induced nephrotoxicity
{[}11{]}. However, CIS nephrotoxicity remains a significant clinical
problem that requires effective solutions. CIS and RAN have opposing
effects mediated by common mechanisms, such as oxidant-antioxidant
enzyme levels. Therefore, we aimed to evaluate the protective and
therapeutic effects of RAN against CIS-induced nephrotoxicity in terms
of oxidative stress, renal function markers, and histopathological
parameters.

\textbf{MATERIAL-METHOD}

The study used 32 male Sprague Dawley rats weighing between 250-300 g
and aged 4-6 months. The rats were obtained from the \selectlanguage{polish}İ\selectlanguage{english}n\selectlanguage{ngerman}önü University
Experimental Animals Production and Research Center and were housed in a
temperature (21±2°C) and humidity (60±5\%) controlled room with a 12:12
h light: dark cycle. The rats were fed a standard chow pellet diet and
had access to pelleted diet and drinking water ad libitum. The study
protocol was approved by the Ethics Committee on Animal Research under
the Faculty of Medicine at \selectlanguage{polish}İ\selectlanguage{english}n\selectlanguage{ngerman}önü University, Malatya, Türkiye (protocol
no: 2019/A-21). All experimental procedures were carried out by
investigators that blinded the experimental groups and in accordance
with the ARRIVE guidelines {[}12{]}.

A simple randomization technique was used to assign animals to the
experimental groups (n=8 for each group):

\emph{Control group:} A single dose of 2 mL saline was intraperitoneally
(i.p.) administered, and the experiment was terminated 72 hours later.

\emph{CIS group:} A single dose of 8 mg/kg CIS was i.p. administered,
and the experiment was terminated 72 hours later.

\emph{RAN+CIS group:} The rats were given 50 mg/kg RAN orally for 5
days, and a single dose of 8 mg/kg CIS was administered i.p. on the 3rd
day. The experiment was terminated on the 6th day.

\emph{CIS+RAN group:} A single dose of 8 mg/kg CIS was administered i.p.
at baseline, and the rats were given 50 mg/kg RAN orally for 5 days
starting from the 3rd day. The experiment was terminated on the 6th day.

Rat weights were recorded prior to anesthesia. General anesthesia was
induced with 5 mg/kg xylazine and 75 mg/kg ketamine i.p. confirmed with
a finger pinching response. Intracardiac blood samples were collected to
measure biochemical parameters such as blood urea nitrogen (BUN),
creatinine (Cre), albumin, Na\textsuperscript{+}, Cl\textsuperscript{-},
K\textsuperscript{+}, and Ca\textsuperscript{2+}. The blood was
centrifuged at 3000 rpm for 10 minutes, and the serum was separated for
spectrophotometric measurement of biochemical markers in the Architect
C16000 device (Abbott, Chicago, IL, USA) following the manufacturer's
instructions. The right kidneys were removed, weighed on a
high-precision laboratory scale, and stored at -80 degrees for analysis
of tissue biochemistry parameters such as superoxide dismutase (SOD),
catalase (CAT), reduced glutathione (GSH), and malondialdehyde (MDA).
The capsule of the left kidney was carefully peeled, washed with saline,
and kept at room temperature in 10\% formaldehyde-containing boxes for
histopathological analysis.

CISPLATIN DBL 100 mg/ 100 mI Injectable Solution (ORNA, Istanbul) and
Latixa 375 Mg Extended-Release Tablet (Menarini, Istanbul) were used as
the chemical preparations.

\textbf{Histological Analysis}

Following tissue follow-up procedures, 4-5 \selectlanguage{greek}μ\selectlanguage{english}m thick sections were
obtained from the paraffin blocks. The sections were subjected to
hematoxylin-eosin (H\&E) staining to examine general morphological
structures.

Kidney sections were evaluated for tubular degeneration (cast formation,
tubular necrosis, and dilatation) in the cortical and medullary areas.
Ten randomly selected areas were assessed based on the degree of
histological changes and scored as follows: 0 for no change, 1 for mild,
2 for moderate, and 3 for severe changes {[}13{]}.

The analyses were performed using the Leica Q Win Image Analysis System
(Leica Micros Imaging Solutions Ltd., Cambridge, UK) with the Leica
DFC-280 research microscope.

\textbf{Biochemical Analysis}

Protein determination in the tissue was performed by Biuret protein
analysis using bovine serum albumin as a standard {[}14{]}.

MDA, an indicator of lipid peroxidation, was assessed according to the
method described by Uchiyama and Mihara {[}15{]}. The rat kidney sample
was homogenized in a 1.15\% KCl solution on ice for 1 minute at 15000
rpm to obtain a 10\% homogenate. This homogenate was used directly in
the MDA analysis, and the results were expressed as nmol/gram tissue.

GSH was determined according to Ellman's method {[}16{]}. The rat kidney
sample was homogenized on ice to form a 10\% homogenate at 15000 rpm for
1-2 minutes. The homogenate was then centrifuged at 3000 rpm, +4
degrees, for 15 minutes. The resulting supernatant TCA solution was
added, mixed, and centrifuged again, making the sample ready for GSH
analysis, and the results were expressed as nmol/g tissue.

Tissue SOD activity was measured according to the method described by
Sun et al. {[}17{]}. The rat kidney sample was homogenized on ice for 1
minute at 15000 rpm to obtain a 10\% homogenate. The homogenate was then
centrifuged at 10000 rpm for 20 minutes. A 3:5 ratio of
chloroform/ethanol (3 parts chloroform to 5 units of ethanol) was added
to the supernatant, and the samples were centrifuged again at 5000 rpm
at +4 degrees for 20 minutes. The top clear white chloroform phase was
carefully taken with a pipette and used in Cu/Zn-SOD analysis. The
enzyme activity was expressed as U/g protein.

Tissue CAT activity was measured according to Luck's method {[}18{]}.
The rat kidney sample was homogenized on ice for 1 minute at 15000 rpm
to obtain a 10\% homogenate. The homogenate was then centrifuged at
10000 rpm for 20 minutes and used for the supernatant CAT analysis. The
results were presented as K/g protein.

\textbf{Statistical Analysis}

The statistical analysis was conducted using the statistical software
developed by the Department of Biostatistics and Medical Informatics at
\selectlanguage{polish}İ\selectlanguage{english}n\selectlanguage{ngerman}önü University, Faculty of Medicine, Malatya, Türkiye {[}19{]}.
Normality tests showed that the measurable variables in all groups did
not follow a normal distribution. Therefore, the Kruskal-Wallis analysis
of variance, a non-parametric test, was used to compare the groups for
all variables. The Mann-Whitney-U test with Bonferroni correction was
used to compare between the two groups. Statistical significance was
considered at p\textless{}0.05. The data were presented as mean with
95\% confidence interval (lower-upper bound).

\textbf{RESULTS}

\textbf{Death and Weight}

During the course of the experiment, it was observed that three rats
expired within the CIS+RAN group. In order to achieve uniformity in
sample size across all groups and to obtain sufficient data for
statistical analysis, three additional rats were included in the same
group. Upon completion of the experiment, the weights of the rats and
their respective kidneys were measured. Notably, no statistically
significant differences were observed among the groups
(p\textgreater{}0.05) (Figure 1).

\textbf{Kidney Function Tests}

\textbf{-BUN and Cre}

Upon further examination of the results, it was observed that there was
a significant increase in BUN and Cre values among all groups that were
administered with CIS (CIS, CIS+RAN, RAN+CIS), as compared to the
control group (p\textless{}0.05). Furthermore, a significant decrease in
BUN values (p\textless{}0.05) was observed in the CIS group, as compared
to the CIS+RAN group. However, no significant differences in Cre values
were noted among the groups (p\textgreater{}0.05) (Figure 2).

\textbf{-Electrolytes and Albumin}

The electrolytes Na\textsuperscript{+}, Cl\textsuperscript{-},
K\textsuperscript{+}, and Ca\textsuperscript{2+} were measured to
evaluate the filtration capacity of the kidneys. However, neither the
administration of CIS nor therapeutic RAN produced any significant
differences among the groups (p\textgreater{}0.05).

Serum albumin values in the CIS group showed a non-significant decrease
as compared to the control group (p\textgreater{}0.05). Conversely,
albumin levels were significantly increased in the CIS+RAN group, as
compared to the CIS group (p\textless{}0.05) (Figure 2).

\textbf{Histopathological Findings}

The renal tissue in the control group exhibited a normal histological
appearance (Figure 3A). In contrast, the CIS group displayed cortical
and medullary tubular degenerative changes, necrosis of epithelial cells
in cortical tubules, and dilatation of medullary tubules, along with
caste formation observed in the lumen of some tubules (Figure 3B).
Notably, the differences between the control and CIS groups were found
to be statistically significant (p\textless{}0.0001).

In the RAN+CIS group, the observed histopathological changes were
significantly reduced as compared to the CIS group (p\textless{}0.0001)
(Figure 3C). However, degenerative changes in the tubules persisted, and
the severity of tubular degeneration, especially tubular dilatation, was
significantly higher in the CIS+RAN group than in the CIS group
(p\textless{}0.0001) (Figure 3D). The histopathological evaluation
results of the groups are presented in Figure 3E.

\textbf{Tissue Biochemistry}

MDA, a biomarker that indicates oxidative stress as a lipid peroxidation
product, showed a significant increase in the CIS group as compared to
the Control group (p\textless{}0.05). Intriguingly, MDA levels were
significantly higher in the RAN+CIS group than in the CIS and CIS+RAN
groups (p\textless{}0.05) (Figure 4).

SOD, CAT, and GSH are antioxidant enzymes that work to prevent damage
caused by ROS and take part in different enzymatic steps to render these
radicals harmless. SOD levels were decreased in the CIS and RAN+CIS
groups, as compared to the Control group, but increased nonsignificantly
in the CIS+RAN group (p\textgreater{}0.05). CAT and GSH values were
similar among groups (p\textgreater{}0.05) (Figure 4).

\textbf{DISCUSSION}

The kidney plays vital roles in maintaining homeostasis, including the
regulation of water and electrolyte balance and the elimination of
endogenous and exogenous metabolites {[}20{]}. Despite the known
nephrotoxicity of CIS since its introduction to the market many years
ago, it continues to be widely prescribed, despite efforts to find less
toxic but equally effective alternatives {[}21{]}. CIS-induced
nephrotoxicity is associated with oxidative stress, which plays a
significant role in the pathogenesis of the condition {[}1, 4{]}.

Numerous studies have demonstrated that CIS-induced nephrotoxicity
causes a decrease in kidney function, with an increase in serum
creatinine and BUN levels. For instance, in a clinical trial involving
400 patients, serum creatinine reached the upper limit of normal during
follow-up in 42\% of patients after CIS administration, which was
defined as nephrotoxicity {[}22{]}. Consistent with the literature, our
study showed that BUN and creatinine levels increased in the CIS group
but remained similar in the other groups {[}23{]}. Furthermore, a study
showed that prophylactic administration of RAN preserved BUN and
creatinine values in patients with contrast-induced kidney damage. The
protective effect of RAN on renal function can be attributed to its
modulation of intracellular Ca2+ homeostasis, oxidative stress, and
suppression of apoptosis {[}24{]}.

Research findings indicate that CIS irreversibly binds to albumin, a
plasma protein {[}25{]}. Consequently, predicting the safe drug range in
tissues based on plasma CIS levels is challenging. Burns et al. proposed
a clinical risk score algorithm that incorporated patient age, dosage,
hypertension, and albumin levels to forecast CIS nephrotoxicity
{[}26{]}. Another study found a correlation between low pre-treatment
albumin levels and neutropenia after CIS treatment {[}27{]}. However,
albumin was regarded as a risk parameter rather than a marker of
nephrotoxicity. In our investigation, no significant changes in albumin
levels were observed.

The renal tubules regulate the serum levels of electrolytes by
reabsorbing them. In an experimental study on CIS nephrotoxicity, renal
losses were believed to be the cause of hypomagnesemia, hypocalcemia,
and hypokalemia {[}28{]}. Goren et al. noted that electrolyte imbalances
may be influenced by the cumulative dose of CIS {[}29{]}. It is possible
that the study design did not induce cumulative dose toxicity, which may
explain why other electrolytes did not change as expected. Additionally,
Oronsky et al. conducted an extensive review of CIS and electrolyte
disorders {[}30{]}. The variability in electrolyte levels may be due to
their different mechanisms and presence in various tissues (e.g., Ca2+
is influenced by parathormone and vitamin D, and losses occur from bone
to kidney and intestine) and measurement methods. A clinical study
demonstrated a significant reduction in the incidence of nephrotoxicity
with the administration of Mg, Ca, and K supplements during CIS
treatment {[}31{]}. Moreover, in their study, Ma et al. evaluated
intracellular Na flow by confocal microscopy, which contributed to the
renoprotective effect of RAN due to its impact on the late
Na\textsuperscript{+} channel {[}24{]}.

The formation and removal of ROS must be balanced to prevent oxidative
stress. Disturbance of this balance can lead to oxidative stress,
emphasizing the importance of measuring it with appropriate biomarkers
and treating it with suitable antioxidant substances {[}32{]}. MDA is
among the most commonly used markers of oxidative stress, as it
indicates lipid peroxidation. Non-enzymatic elements of the antioxidant
system that help reduce ROS levels include GSH, vitamin C, and E, while
enzymatic antioxidants comprise SOD, CAT, and GSH {[}33-35{]}.

Yu et al. investigated the effectiveness of Hesperetin against CIS
nephrotoxicity, utilizing techniques such as Western blot analysis,
fluorescence staining, and tissue biochemistry similar to those in our
study. Additionally, inflammation and apoptosis were responsible for
CIS-induced renal damage {[}36{]}. Our findings were consistent with
their results, as MDA levels were among the increased oxidant parameters
in CIS-administered rats {[}37, 38{]}. Furthermore, a study examining
the antidiabetic effect of RAN demonstrated a significant decrease in
MDA levels in pancreatic tissue {[}39{]}. However, in another study, RAN
did not cause changes in MDA levels in rat hearts {[}40{]}.

Superoxide anion, hydrogen peroxide, and hydroxyl radical are substances
that play a significant role in CIS-induced organ damage {[}41{]}. SOD,
CAT, and GSH are enzymatic antioxidants that convert these harmful
substances into harmless forms through different enzymatic steps
{[}33{]}. In a study by Ehsan et al., Casticin was used as an
antioxidant against CIS-induced renal toxicity. They found that Casticin
application increased the levels of SOD, CAT, and GSH, which were
reduced by CIS. Additionally, the levels of thiobarbituric acid reactive
substances, hydrogen peroxide, kidney injury molecule-1, and neutrophil
gelatinase-associated lipocalin that they examined also supported their
hypothesis {[}42{]}. Similarly, in a lung malignancy study where the
antioxidant effect of RAN at doses of 50 and 100 mg was measured using
MDA, SOD, CAT, and GSH, a significant decrease was observed in MDA
values, and an increase in the antioxidant parameters SOD, CAT, and GSH
compared to the malignancy group. These findings suggested the
protection of RAN through a dose-dependent antioxidant mechanism, as
reported in the literature {[}43{]}. Based on these results, we believe
that further studies could demonstrate the same antioxidant effect on
the kidney.

ROS can disrupt mitochondrial permeability and lead to cell necrosis and
apoptosis. In the context of acute kidney injury caused by ischemia and
nephrotoxic agents, ROS is considered an early pathological factor
{[}44{]}. In our study, we observed necrosis in the cortical tubule
epithelium and dilatation in the medullary tubules, accompanied by caste
formation in some tubules, upon histopathological examination of the
kidney tissue at the end of the study period. These findings are
consistent with the results of a study by Parlakpinar et al. where
necrosis and tubular dilatation were also observed in the tubule
epithelium {[}45{]}. RAN was administered as a pre-treatment against
contrast-induced kidney damage in a study where histopathological
changes were found to be improved {[}24{]}. In our study, we observed
that there was no significant difference in damage between the CIS+RAN
group and the CIS group, with a nonsignificant increase in the degree of
dilatation observed in the former group.

\textbf{CONCLUSION}

In sum, our study confirmed the nephrotoxicity of CIS through analysis
of various biochemical and histopathological parameters, which suggested
an imbalance in oxidant and antioxidant levels leading to oxidative
stress. While the effects of RAN treatment/prophylaxis were not
consistently observed across all parameters, the improvement in kidney
function highlights the need for further and more comprehensive studies
on the potential benefits of RAN.

\textbf{Acknowledgments}

This work was supported by the Scientific and Technological Research
Council of Turkey under Grant {[}2209-A/1919B011900466{]}.

\textbf{Declaration of Interest Statement}

The authors report there are no competing interests to declare.

\textbf{Data Availability Statement}

The data that support the findings of this study are available from the
corresponding author, {[}AB{]}, upon reasonable request.

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\textbf{Figure Legends}

\textbf{Figure 1.} Rat and kidney weights evaluated in the study.

\textbf{Figure 2.} Renal function parameters and electrolytes analyzed
in the study.

\textbf{Figure 3.} Representative images of histological evaluation of
renal cortical tissue. (A) Control group with normal histological
appearance. (B) CIS group showing necrotic changes (arrowheads) and
dilatation (arrows) in renal tubules. (C) RAN+CIS group exhibiting a
significant decrease in degenerative changes in tubules (arrowheads)
compared to the CIS group. Notably, tubular degeneration was more severe
in the CIS+RAN group (D) than in the CIS group. H-E staining,
magnification x20.

\textbf{Figure 4.} Tissue oxidant and antioxidant parameters measured in
the study.\selectlanguage{english}
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