Cisplatin Nephrotoxicity Research Articles

3-deazaneplanocin A protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression

3-deazaneplanocin A (3-DZNeP) has been used as an inhibitor of enhancer of zeste homolog 2 (EZH2). Here, we explore the role and underlying mechanisms action of 3-DZNeP in abrogating cisplatin nephrotoxicity. Exposure of cultured mouse renal proximal tubular epithelial cells (mTECs) to cisplatin resulted in dose and time-dependent cleavage of caspase-3, decrease of cell viability, and increase of histone H3 lysine 27 trimethylation (H3K27me3), whereas expression levels of EZH2, a major methyltransferase of H3K27me3, were not affected. Treatment with 3-DZNeP significantly inhibited cisplatin-induced activation of caspase-3, apoptosis, loss of cell viability but did not alter levels of EZH2 and H3K27me3 in cultured mTECs. 3-DZNeP treatment did not affect activation of extracellular signal-regulated kinase (ERK) 1/2, p38 or c-Jun N-terminal kinases (JNK) 1/2, which contribute to renal epithelial cell death, but caused dose-dependent restoration of E-cadherin in mTECs exposed to cisplatin. Silencing of E-cadherin expression by siRNA abolished the cytoprotective effects of 3-DZNeP. In contrast, 3-DZNeP treatment potentiated the cytotoxic effect of cisplatin in H1299, a non-small cell lung cancer cell line that expresses lower E-cadherin levels. Finally, administration of 3-DZNeP attenuated renal dysfunction, morphological damage, and renal tubular cell death, which was accompanied by E-cadherin preservation, in a mouse model of cisplatin nephrotoxicity. Overall, these data indicate that 3-DZNeP suppresses cisplatin-induced tubular epithelial cell apoptosis and acute kidney injury via an E-cadherin-dependent mechanism, and suggest that combined application of 3-DZNeP with cisplatin would be a novel chemotherapeutic strategy that enhances the anti-tumor effect of cisplatin and reduces its nephrotoxicity.

Intervention of mitochondrial activity attenuates cisplatin-induced acute kidney injury.

The dysfunction of mitochondrial respiratory chain induced by cisplatin results in overproduction of reactive oxygen species (ROS) which contributes to kidney injury. The current study aimed to evaluate the effect of a mitochondrial electron transport inhibitors of rotenone (mitochondrial complex I inhibitor) and azoxystrobin (mitochondrial complex III inhibitor), in cisplatin-induced kidney injury. In vivo, cisplatin was administered to male C57BL/6J mice by a single intraperitoneal (i.p.) injection (20mg/kg). Then the mice were treated with or without 200ppm rotenone in food. Mice were sacrificed after cisplatin administration for 72h. The serum and the kidney tissues were collected for further analysis. In vitro, mouse proximal tubular cells (mPTCs) were treated with cisplatin (5µg/mL) and rotenone/azoxystrobin for 24h. Flow cytometry, Western blotting, and TUNEL staining were used to evaluate the cell injury. In vivo, rotenone treatment obviously ameliorated cisplatin-induced renal tubular injury evidenced by the improved histology and blocked NGAL upregulation. Meanwhile, cisplatin-induced renal dysfunction shown by the increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C were significantly reduced by rotenone treatment. Moreover, the increments of cleaved caspase-3 and transferase dUTP nick-end labeling (TUNEL)-positive cells were markedly decreased in line with the attenuated mitochondrial dysfunction and oxidative stress after rotenone administration. In vitro, rotenone and azoxystrobin protected against mitochondrial dysfunction, oxidative stress, and renal tubular cell apoptosis induced by cisplatin. Our results demonstrated that inhibition of mitochondrial activity significantly attenuated cisplatin nephrotoxicity possibly by inhibiting mitochondrial oxidative stress.

ROLE OF BEE POLLEN AND SILYMARIN IN AMELIORATION OF PROXIMAL RENAL TUBULAR ACIDOSIS CAUSED BY CISPLATIN

Proximal renal tubular acidosis (RTA), a disorder in acid-base balance in the kidney is characterized by loss of bicarbonate ions in urine. One of its causes is the production of free radicals by cisplatin (CP). Therefore, the protective effects of silymarin and bee pollen as antioxidant natural product treatments were evaluated against proximal RTA induced by CP in male albino rats. Rats were divided into 8 groups (7 rats each); control group, cisplatin group, bee pollen group, silymarin group, cisplatin then bee pollen group, cisplatin then silymarin group, bee pollen then cisplatin group and silymarin then cisplatin group. After 12 days (the experiment period), sera were used to determine kidney function parameters (urea, uric acid, and creatinine), protein parameters (total protein, albumin, and globulin), and blood glucose level. While anticoagulant was added to the blood to determine acid-base balance and hematological parameters. Silymarin and bee pollen improved the kidney dysfunction in the CP rats group through decreasing levels of kidney function parameters and increasing levels of serum proteins. They also returned the blood glucose level and the hematological parameters in the CP rats group to the normal values. While the acid-base balance parameters were ameliorated after using silymarin and bee pollen against CP nephrotoxicity. So, we conclude that silymarin and bee pollen can be used to ameliorate the proximal RTA and anemia induced by CP.

Pre-treatment with Empagliflozin ameliorates Cisplatin induced acute kidney injury by suppressing apoptosis

Dose-limiting nephrotoxicity restricts Cisplatin use in high therapeutic doses. Empagliflozin showed a reno-protective effect in diabetic nephropathy. We investigated if Empagliflozin can ameliorate Cisplatin nephrotoxicity whether used prophylactically or therapeutically. Forty male Wistar rats were divided into 5 groups: (1) control; (2) Cisplatin-induced nephrotoxicity by single intraperitoneal dose; (3) Empagliflozin was given for 10 days before a single dose of Cisplatin; (4) a single dose of Cisplatin followed by Empagliflozin for 10 days; (5) received Empagliflozin only. Regular assessment of weight was done, biochemical evaluation for serum urea, creatinine, uric acid, albumin, and glucose was performed, kidney tissue nerve growth factor-β (NGF-β) and oxidative stress parameters were measured, kidneys were evaluated histopathologically and immunostained for caspase 3. Cisplatin significantly reduced body weight, NGF-β, and reduced glutathione, elevated urea, creatinine, and malondialdehyde with no effect on other serum biochemical parameters. Histopathologically, there was high acute tubular necrosis (ATN) score with strong immunostaining of caspase 3. The use of Empagliflozin significantly reduced urea and creatinine in both prophylactic and therapeutic, reduced ATN score in the prophylactic group associated with minimal staining of caspase 3 and elevated reduced glutathione. In conclusion, prophylactic Empagliflozin protected against Cisplatin-induced acute kidney injury mainly via anti-apoptotic effect.

Nephroprotective Effect of Embryonic Stem Cells Reducing Lipid Peroxidation in Kidney Injury Induced by Cisplatin.

Introduction The acute kidney injury (AKI) is characterized by a sudden glomerular filtration reduction. Renal or intrinsic causes of AKI include nephrotoxicity induced by exogenous agents like cisplatin, which causes oxidative stress altering the biochemical process and leading to apoptosis. Therefore, this research is aimed at analyzing the embryonic stem cells (ESC) nephroprotective effect in AKI induced by cisplatin, employing genetic, phenotypic, and microspectroscopic techniques. Methods Thirty mice were randomly divided into three groups (n = 10): the healthy, isotonic salt solution (ISS), and mouse embryonic stem cells (mESC) groups. The ISS and mESC groups were subjected to AKI using cisplatin; 24 h post-AKI received an intraperitoneal injection of ISS or 1 × 106 mESC, respectively. At days 4 and 8 post-AKI, five mice of each group were sacrificed to analyze the histopathological, genetic (PDK4 and HO-1), protein (p53), and vibrational microspectroscopic changes. Results Histopathologically, interstitial nephritis and acute tubular necrosis were observed; however, the mESC group showed a more preserved microarchitecture with high cellularity. Additionally, the PDK4 and HO-1 gene expression only increased in the ISS group on day 4 post-AKI. Likewise, p53 was more immunoexpressed at day 8 post-AKI in the ISS group. About biomolecular analysis by microspectroscopy, bands associated with lipids, proteins, and nucleic acids were evidenced. Besides, ratios related to membrane function (protein/lipid), unsaturated lipid content (olefinic/total lipid, olefinic/total CH2, and CH2/CH3), and lipid peroxidation demonstrated oxidative stress induction and lipid peroxidation increase mainly in the ISS group. Finally, the principal component analysis discriminated against each group; nonetheless, some data of the healthy and mESC groups at day 8 were correlated. Conclusions The mESC implant diminishes cisplatin nephrotoxicity, once the protective effect in the reduction of lipid peroxidation was demonstrated, reflecting a functional and histological restoration.

The effect of white tea on serum TNF-α/NF-κB and immunohistochemical parameters in cisplatin-related renal dysfunction in female rats

ObjectiveNephrotoxicity is the most important side effect of the antineoplastic drug cisplatin, thereby restricting its use. The aim of this study was to investigate the protective effects of white tea infusions (WT) against renal damage induced by cisplatin (CP) in rats by biochemical and histopathological means. Materials and methodsThis study used 24 female Sprague Dawley rats at 12–14 weeks of age and weighing 250–300 g. Rats were divided into three groups: Control, CP and CP + WT groups. CP was injected 7 mg/kg i.p as a single dose/rat in the CP group. White tea was given at a dose of 0.5% (w/v) for 4 weeks. At the end of the experiment, blood urea nitrogen (BUN), creatinine, uric acid, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nuclear factor kappa B (NF-κB) along with caspase-3 in the kidney were evaluated in study. ResultsBUN, creatinine, TNF-α, NF-κB and IL-6 levels of the CP group showed a statisically significant increase in comparison to the control group. TNF-α, NF-κB and IL-6 levels showed a statistically significant decrease in the CP + WT group with respect to the CP group. Caspase-3 levels in tubular epithelial cells decreased in CP + WT group compared with CP group (p = 0.02). ConclusionWhite tea infusions reduced significantly the nephrotoxicity of CP. The anti-nephrotoxic feature of the infusion may be attributed primarily to its anti-inflammatory and anti-apoptotic characteristics.

Protease-activated receptor 2 exacerbates cisplatin-induced nephrotoxicity.

Acute kidney injury (AKI) is associated with hypercoagulability. Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade activate protease-activated receptor 2 (PAR2). Previously, we have shown that PAR2-mediated inflammation aggravates kidney injury in models of diabetic kidney disease and adenine-induced renal fibrosis. However, the role of PAR2 in AKI remains unclear. To clarify the role of PAR2, we administered cisplatin, one of the most common causal factors of AKI, to wild-type and PAR2-deficient mice. The expression levels of tissue factor and PAR2 were significantly increased in the kidneys of mice that were administered cisplatin. A lack of PAR2 corrected the levels of plasma blood urea nitrogen and creatinine as well as ameliorated the acute tubular injury score in the kidney. A lack of PAR2 corrected the infiltration of neutrophils and the gene expression levels of proinflammatory cytokines/chemokines in these mouse kidneys. Similarly, apoptotic markers, such as cleaved caspase-3-positive area and Bax/Bcl2 ratio, were attenuated via PAR2 deletion. Thus, elevated PAR2 exacerbates cisplatin nephrotoxicity, and targeting PAR2 is a novel therapeutic option that aids in the treatment of patients with cisplatin-induced AKI.

Role of pea protein hydrolysates as antinephrotoxicity

Introduction: Renal damage can be caused by various causes. One of them is drugs that are toxic to the renal, such as cisplatin (CP). In an attempt to find a remedy for antinephrotoxicity, several hydrolyzed proteins were investigated. This study was conducted to find out the effects of 8 peas protein hydrolysates (PPH) hydrolyzed using simple procedure to renal organ indexes (OIs) and histopathological features of CP-induced nephrotoxicity Wistar rats. Materials and Methods: Protein hydrolysates of yellow peas, gude beans, green peas, and pea protein isolate (PPI) which hydrolyzed using neutrase or bromelain were administered to 50 female Wistar rats. The treatments were given for 30 days, and on day 7, all groups of rats, except negative control group, were injected CP intraperitoneal. Renal OIs were measured and kidneys were histopathological analyzed, which the results were converted to scoring system. Data were analyzed using ANOVA, LSD, Kruskal–Wallis, and Mann–Whitney test. Results: Data of renal OIs were homogenous and normally distributed but were not significantly different between groups (P > 0.05).The nephrotoxicity of CP were not changing the renal OI but worsen the histopathological features of renal tubules in CP-induced rats (P < 0.01). All protein hydrolysate treatment groups showed less histopathological score than CP group. Green PPH hydrolyzed by bromelain-treatment group showed the lowest scores. Conclusion: All PPH hydrolized with neutrase or bromelain improve the CP-induced nephrotoxicity rats. Green PPH with bromelain hydrolyzed had a promising potency as antinephrotoxicity.

The effect of N-acetylcysteine on inflammation and oxidative stress in cisplatin-induced nephrotoxicity: a rat model

Background/AimCisplatin is a highly effective chemotherapeutic agent used in the treatment of solid organ cancers. Besides its chemotherapeutic effectiveness, cisplatin administration is associated with numerous side effects. Of those, the most clinically significant and common effect is nephrotoxicity. Recent studies reported that oxidative stress and inflammation are probably the most important mechanisms that contribute to the nephrotoxicity. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent. In the present study, the effects of NAC on cisplatin-induced nephrotoxicity were investigated.Materials and methodsRats were divided into four groups each including eight rats: CONT, NAC-250, CP, and CP+NAC. Rats in experimental groups were treated intraperitoneally (i.p.) with a single dose of cisplatin (10 mg/kg body weight) and i.p. with NAC (250 mg/kg body weight) for three consecutive days. Nephrotoxicity was determined by plasma BUN and creatinine levels. In tissue samples, myeloperoxidase (MPO), nuclear factor-kappa B (NF-kB), high mobility group box-1 (HMGB-1), total oxidant status (TOS), and total antioxidant status (TAS) levels were measured. Kidneys were analyzed histopathologically as well.ResultsIt was revealed that cisplatin was not effective on MPO, HMGB-1 and NF-kB levels but did increase TOS levels and decrease TAS levels in tissue samples. Interestingly, NAC elevated MPO and HMGB-1 levels significantly. Nevertheless, NAC ameliorated histological and functional changes in kidney tissues.ConclusionIt is suggested that inflammation has a limited effect on cisplatin nephrotoxicity in this experimental design, and, as reflected by decreased BUN and creatinine levels, NAC can be used as an additional therapeutic agent in standard cisplatin treatment protocols.

MDM2 inhibitor ameliorates cisplatin-induced nephropathy via NFκΒ signal inhibition.

Cisplatin is a platinum‐containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co‐transcription factor for nuclear factor‐κB (NFκB), whose signaling can be involved in cisplatin‐induced tubular injury. We therefore examined the effects of MDM2 inhibitor on cisplatin cytotoxicity. In order to induce acute kidney injury and to investigate MDM2 inhibitory effects, we injected cisplatin into rats with or without the MDM2 inhibitor, DS‐5272, and analyzed kidney physiology/histology and NFκB signaling. Serum creatinine was significantly lower in the DS‐5272 group than in the vehicle group on day 3 (0.55 ± 0.069 vs 0.70 ± 0.072 mg/dL, P < 0.05). DS‐5272 also significantly decreased kidney injury molecule‐1 (KIM‐1) expression, improved tubular injury, and decreased apoptotic cells. Western blotting showed that cisplatin increased NFκB phosphorylation in kidneys, which was significantly suppressed by DS‐5272. In vitro, we treated HEK 293 cells with cisplatin, in the absence or presence of DS‐5272, and examined cytotoxicity and NFκB transcriptional activity. DS‐5272 co‐treatment reduced both cisplatin‐induced cell death and NFκB transcriptional activity. Collectively, these findings suggest that DS‐5272 can ameliorate cisplatin nephrotoxicity via NFκB signal inhibition.

PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury

Cisplatin is a widely used chemotherapeutic drug with notorious toxicity in the kidneys, which involves mitochondrial dysfunction and damage in renal tubular cells. Mitophagy is a form of selective autophagy that removes damaged or dysfunctional mitochondria to maintain cellular homeostasis. In this study, we have used mouse and cell models to examine the role and regulation of mitophagy in cisplatin nephrotoxicity. Cisplatin treatment was associated with the activation of autophagy and mitophagy. Rapamycin, a pharmacological inhibitor of mTOR, stimulated autophagy and mitophagy, and alleviated the development of cisplatin nephrotoxicity. PINK1 and Parkin were increased in kidney tissues during cisplatin treatment of mice. In PINK1 or Parkin gene knockout mouse models, both basal and cisplatin-induced mitophagy in kidneys were defective. Compared with wild-type littermates, PINK1 and Parkin knockout mice showed more severe renal functional loss, tissue damage, and apoptosis during cisplatin treatment. The results suggest that PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity and has a protective role against kidney injury.

A conveniently synthesized Pt (IV) conjugated alginate nanoparticle with ligand self-shielded property for targeting treatment of hepatic carcinoma

The clinical translation remains a major challenge for platinum drug loaded nanoparticle due to the complexity of composition and preparation. Here we employed only three ingredients to prepare Pt (IV) prodrug-loaded ligand-induced self-assembled nanoparticles (GA-ALG@Pt NPs) via facile one-pot route for liver tumor treatment. GA-ALG@Pt NPs were found equipped with intelligently ligand self-shielded property in which the internal GA could be induced to expose by initial cellular recognition, resulting in strengthened cellular uptake (20%-30%) and prolonged blood circulation time (3.43 times). Appreciable tumor targeting ability (2 times) and especially tumor selectivity (2.5 times) were obtained. Glutathione-triggered release of therapeutic agent generated satisfactory antitumor effect. Bio-safety is also a distinguishing feature of GA-ALG@Pt NPs that greatly relief the nephrotoxicity and systematic toxicity of cisplatin. This conveniently synthesized nanoparticle processes superior targeting capacity and biosecurity, supplying an effective approach to translational cancer therapy in the future.

Celastrol ameliorates cisplatin nephrotoxicity by inhibiting NF-κB and improving mitochondrial function.

BackgroundCelastrol is an active ingredient of Chinese medicine Tripterygium wilfordii which is clinically used to treat the immune diseases. Currently, celastrol is documented as a potent agent for treating cancer and inflammatory disorders. This study was to investigate the effect of celastrol on cisplatin nephrotoxicity and the underlying mechanism.MethodsMale C57BL/6 mice were treated with cisplatin (20 mg/kg) with or without celastrol treatment (1 and 2 mg/kg/day). In vitro, human proximal tubule epithelial cell line (HK−2) and mouse renal tubule epithelial cells (RTECs) were treated with cisplatin (5 μg/mL) with or without celastrol administration. Then renal injury and cell damage were evaluated.FindingsIn vivo, after celastrol treatment, cisplatin-induced kidney injury was significantly ameliorated as shown by the improvement of renal function (BUN, serum creatinine, and cystatin C), kidney morphology (PAS staining) and oxidative stress (MDA) and the suppression of renal tubular injury markers of KIM-1 and NGAL. Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in celastrol-treated mice. In vitro, celastrol treatment markedly inhibited cisplatin-induced renal tubular cell apoptosis, suppressed NF-κB activation, and improved mitochondrial function evidenced by the restored mtDNA copy number, mitochondrial membrane potential, and OXPHOS activity in cisplatin-treated renal tubular epithelial cells.InterpretationThis work suggested that celastrol could protect against cisplatin-induced acute kidney injury possibly through suppressing NF-κB and improving mitochondrial function.FundThe National Natural Science Foundation of China, National Key Research and Development Program, and Natural Science Foundation of Jiangsu Province.

Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review.

Background: Nephrotoxicity is a notable adverse effect in cisplatin treated patients characterized by tubular injury and/or increased serum creatinine (SCr) with incidence varying from 20 to 70%. Pharmacogenomics has been shown to identify strongly predictive genetic markers to help determine which patients are more likely to experience, for example, a serious adverse drug reaction or receive optimal benefit through enhanced efficacy. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; however, a comprehensive overview is lacking.Methods: A systematic review was performed using Pubmed, Embase and Web of Science on clinical studies that used cisplatin-based chemotherapy as treatment, had available genotyping data, and evaluated nephrotoxicity as an outcome. The quality of reporting was assessed using the STrengthening the REporting of Genetic Association Studies (STREGA) checklist.Results: Twenty-eight eligible studies were included; all were candidate gene studies. Over 300 SNPs across 135 genes were studied; 29 SNPs in 14 genes were significantly associated with cisplatin-induced nephrotoxicity. A variation in SLC22A2 rs316019, a gene involved in platinum uptake by the kidney, was associated with different measures of nephrotoxicity in four independent studies. Further, variants of ERCC1 (rs11615 and rs3212986) and ERCC2 (rs13181), two genes involved in DNA repair, were found to be positively associated with increased risks of nephrotoxicity in two independent studies.Conclusion: Three genes consistently associated with cisplatin-induced nephrotoxicity. Further research is needed to assess the biological mechanism and the clinical value of modifying treatment based on SLCC22A2 and ERCC1/2 genotypes.

Cisplatin-Induced Rodent Model of Kidney Injury: Characteristics and Challenges.

Cisplatin is an antitumor drug used in the treatment of a wide variety of malignancies. However, its primary dose-limiting side effect is kidney injury, which is a major clinical concern. To help understand mechanisms involved in the development of kidney injury, cisplatin rodent model has been developed. Given the complex pathogenesis of kidney injury, which involves both local events in the kidney and interconnected and interdependent systemic effects in the body, cisplatin rodent model is indispensable in the investigation of underlying mechanisms and potential treatment strategies of both acute and chronic kidney injury. Cisplatin rodent model is well appreciated and widely used model due to its simplicity. It has many similarities to human cisplatin nephrotoxicity, which are mentioned in the paper. In spite of its simplicity and wide applicability, there are also traps that need to be taken into account when using cisplatin model. The present paper is aimed at giving a concise insight into the complex characteristics of cisplatin rodent model and heterogeneity of cisplatin dosage regimens as well as outlining factors that can severely influence the outcome of the model and the study. Challenges for future research are also mentioned.

Ameliorative effect of selenium nanoparticles and fish oil on cisplatin and gamma irradiation-induced nephrotoxicity in male albino rats

Cisplatin (CP) is a major antineoplastic drug for the treatment of solid tumors, however, its clinical utility is limited by nephrotoxicity. Also, radiotherapy is an important treatment modality for many malignancies. The present studies were performed to test whether fish oil (FO) and/or selenium nanoparticles (SeNPs) administration have an ameliorative effect on CP and γ-irradiation induced nephrotoxicity. FO and/or SeNPs were administered to male albino rats daily for 12 days before being intraperitoneally injected with a single dose of CP (10 mg/kg body weight) and whole body exposed to a single dose of γ-radiation (0.7 Gy). Biochemical analysis and histopathological examination were performed. Pretreatment with FO and/or SeNPs before the administration of CP and exposure to γ-radiation significantly reduced CP- and γ-radiation-induced high levels of serum urea and creatinine and renal tumor necrosis factor-α, caspase-3 and cyclooxygenase-2, also they significantly prevented renal total antioxidant capacity levels decrease and ameliorated the levels of most studied trace elements. The histopathological results supported the biochemical findings of this study. The administration of FO and/or SeNPs might be useful for preventing nephrotoxicity which can be caused by CP and radiotherapy during the treatment of various malignancies.

Cisplatin Effects in Lung Adenocarcinoma-bearing Mice, Alone and in Combination with Erlotinib.

Cisplatin causes nephrotoxicity that can lead to the development of acute kidney injury or chronic kidney disease. However, the current mouse model of cisplatin nephrotoxicity is neither physiologically nor clinically relevant. Our goal was to improve upon these deficits by developing a repeated, low-dose regimen of cisplatin and combining it with a transgenic mouse model of lung adenocarcinoma. This overview details how addressing these deficits have improved our understanding of cisplatin-induced kidney injury.

Myelosuppression and Nephrotoxicity Induced by Cisplatin in Female Rats: The Role of Berberine Nanoparticles

Cisplatin (CDDP) is one of the most effective antineoplastic drugs used in chemotherapy, strategies to protect tissues against cisplatin nephrotoxicity is a clinical interest. This study aimed to evaluate the possible protective effect of berberine nanoparticles (BBR-NPs) against cisplatin-induced nephrotoxicity in female rats. Intraperitoneal (IP) injection of cisplatin (8 mg/kg) caused significant decrease in RBC, Hb, Hct, WBC and platelets. Also, cisplatin caused disturbances in kidney function as documented by a significant increase in urea, uric acid, creatinine and MDA, with significant decreases in the total protein, albumin, GSH and total thiol.TNF- , caspase-3, IL-2, IL-6 and IL-1were increased in cisplatin treated group. The histopathological changes in cisplatin group include degeneration and desquamation of tubular epithelial cells, hyaline cast formation, inflammatory cell infiltration and tubular dilation. Oral administration of BBR-NPs at a dose 1mg/kg/day for 30 days after cisplatin produced significant decrease in the levels of urea, uric acid, creatinine, TNF- and caspase-3 as well as kidney MDA with a marked increase in total protein, albumin, GSH, total thiol and repairing the histopathological changes. Scanning microscope of RBC showed the protective effect of BBR-NPs against the different changes induced by CDDP. The present study suggested that the anti-oxidant and anti-inflammatory effects of BBR-NPs may prevent CDDP-induced nephrotoxicity via decreasing the oxidative stress, inhibiting the inflammation and apoptosis.

Absence of Sirt3 aggravates cisplatin nephrotoxicity via enhanced renal tubular apoptosis and inflammation.

Cisplatin-based chemotherapy is commonly used in the treatment of solid tumors; however, this agent is limited by its adverse effects on normal tissues, including the kidneys, ears and peripheral nerves. Mechanisms of cisplatin nephrotoxicity are proposed to involve oxidative stress, inflammation, cellular apoptosis and cell cycle regulation. Sirtuin 3 (Sirt3) is a member of the sirtuin family of NAD+-dependent enzymes with homology to Saccharomyces cerevisiae gene silent information regulator 2. Sirt3 is located in mitochondria and is involved in mitochondrial energy metabolism and function; however, the role of Sirt3 in cisplatin nephrotoxicity remains unclear. In the present study, whether Sirt3 has anti-inflammatory and anti-apoptotic effects on cisplatin-induced nephrotoxicity was investigated in mice. Sirt3 knockout mice (Sirt3(−/−)) and corresponding wild type mice were employed in the present study. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 3 days following cisplatin treatment, blood and kidney tissues were harvested. Renal function and histology were evaluated. Tubular apoptosis, cell adhesion molecule expression, and inflammatory cells were evaluated by immunohistochemistry and western blot analysis. Following the induction of cisplatin nephrotoxicity, renal function was significantly aggravated in Sirt3 knockout (KO) mice. Tubular injury and inflammatory cell infiltration were significantly increased in Sirt3KO mice compared with wild type mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end label-positive tubular cells and renal monocyte chemoattractant protein-1 expression levels were increased in Sirt3KO mice compared with in wild type mice. In summary, the absence of Sirt3 aggravated in renal injury by increasing renal inflammation and tubular apoptosis. The results of the present study suggested that Sirt3 may have an important role in cisplatin-induced nephrotoxicity.

Tempol, a superoxide dismutase mimetic agent, reduces cisplatin-induced nephrotoxicity in rats

Cisplatin (CP) is one of the most potent anti-cancer drugs used against different types of cancer. Its use is limited due to its nephrotoxicity. This study is aimed to evaluate the role of a super oxide dismutase (SOD) mimetic agent, tempol, in protection against CP nephrotoxicity in rats. Animals were divided into four groups: Group-1: Normal control group, Group-2: CP group (single dose of CP 6 mg/kg, i.p.), Group-3 and Group-4: Tempol-treated groups (50 mg/kg p.o. and 100 mg/kg p.o. respectively) daily for a week before CP injection and continued for an additional four days after CP injection. Urine and blood samples were collected for the evaluation of kidney function including serum creatinine, BUN, cystatin-c, and creatinine clearance. In addition, western blotting was used to determine urine lipocalin-2 content. Furthermore, kidney tissue was collected for the determination of oxidative stress markers, caspase-3 expression, and histopathological examination. We noticed that both doses of tempol significantly improved kidney function, which was deteriorated by CP injection. Tempol significantly elevated kidney glutathione (GSH) content and SOD activity, and decreased kidney lipid peroxidation and NOx production. Tempol also significantly decreased kidney caspase-3 expression which was elevated by CP toxicity. Thus, we conclude that tempol can protect against CP nephrotoxicity. We noticed that both doses of tempol are effective in ameliorating CP-nephrotoxicity.