C-phycocyanin attenuates cisplatin-induced nephrotoxicity in mice

Although cisplatin is a highly effective antineoplastic agent, nephrotoxicity is its major clinical problem. Recently, it was reported that Spirulina, a blue-green algae, has potent antioxidant properties. The aim of this study was to establish the possible protective role of C-phycocyanin (PC), one of the active ingredients of Spirulina, against cisplatin-induced nephrotoxicity. This study was carried out using human kidney-2 (HK-2) cells and male C57BL6 mice. Cells and mice were divided into four groups; untreated control group, PC-treated control group, cisplatin-treated group, and PC plus cisplatin-treated group. The molecular, functional, and structural parameters were measured. PC significantly attenuated blood urea nitrogen, serum creatinine, renal histological damages, and apoptotic cell death in cisplatin-treated mice. The cisplatin-induced cell death was significantly attenuated in cells pretreated with PC. PC also significantly attenuated the elevation of p-ERK, p-JNK, and p-p38 induced by cisplatin treatment. The expression of Bax, caspase-9, and caspase-3 in cisplatin-treated cells were also decreased by PC treatment. In conclusion, PC ameliorates cisplatin-induced nephrotoxicity and, at least in part, suppression of p-ERK, p-JNK, p-p38, Bax, caspase-9, and caspase-3 may be involved in this mechanism.     

Metabolomic study of cisplatin-induced nephrotoxicity

We have shown that cisplatin inhibits fatty acid oxidation, and that fibrate treatment ameliorates renal function by preventing the inhibition of fatty acid oxidation and proximal tubule cell death. Urine samples of mice treated with single injection of cisplatin (20 mg/kg body weight) were collected for 3 days and analyzed by 1H-nuclear magnetic resonance (NMR) spectroscopy. In a separate group, urine samples of mice treated with peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand WY were also analyzed by NMR after 2 days of cisplatin exposure. Biochemical analysis of endogenous metabolites was performed in serum, urine, and kidney tissue. Electron microscopic studies were carried out to examine the effects of PPARalpha ligand and cisplatin. Principal component analysis demonstrated the presence of glucose, amino acids, and trichloacetic acid cycle metabolites in the urine after 48 h of cisplatin administration. These metabolic alterations precede changes in serum creatinine. Biochemical studies confirmed the presence of glucosuria, but also demonstrated the accumulation of nonesterified fatty acids, and triglycerides in serum, urine, and kidney tissue, in spite of increased levels of plasma insulin. These metabolic alterations were ameliorated by the use of PPARalpha ligand. Electron microscopic analysis confirmed the protective effect of the fibrate on preventing cisplatin-mediated necrosis of the S3 segment of the proximal tubule. Our study shows that cisplatin-induces a unique NMR metabolic profile in urine of mice that developed acute renal failure, and confirms the protective effect of a fibrate class of PPARalpha ligands. We propose that the injury-induced metabolic profile may be used as a biomarker of cisplatin-induced nephrotoxicity.     

Effect of rosiglitazone on cisplatin-induced nephrotoxicity

Aim: Nephrotoxicity is a major side effect of cisplatin (Cis), a widely used chemotherapeutic drug. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of Cis nephrotoxicity. Rosiglitazone (Ros), a peroxisome proliferator-activated receptor-gamma agonist has been recently demonstrated to regulate inflammation by modulating the production of inflammatory mediators and adhesion molecules. The aim of this study was to evaluate the effect of Ros on the prevention of Cis-induced nephrotoxicity. Methods: Eighteen male Sprague–Dawley rats weighing 150–200 g were included in the study. The rats were randomly divided into three groups: group 1: Cis-treated group; group 2: Cis–Ros-treated group; group 3: saline-treated group. Blood urea nitrogen (BUN) and serum creatinine concentrations were measured. In addition, extent of histological renal tubular injury in each animal was graded histologically. Results: Mean BUN and serum creatinine concentrations were significantly lower in group 3 than in group 1 (p < 0.05) and group 2 (p < 0.05). There were no significant differences in terms of BUN and serum creatinine concentrations between groups 1 and 2 (p > 0.05). Acute tubular injury with karyomegalic changes in corticomedullary junction was significantly higher in groups 1 and 2 than group 3 (p < 0.05). However, there were no significant differences between groups 1 and 2 (p > 0.05). Conclusion: This study indicates that post-insult administration of Ros does not seem to have a beneficial effect on prevention and severity of nephrotoxicity induced by Cis.     

The renoprotective effect of curcumin in cisplatin-induced nephrotoxicity

Abstract

The polyphenol curcumin has several pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer features. In this study, we evaluated the effects of curcumin in cisplatin-induced nephrotoxicity in rats. Male Wistar rats were divided into four groups: (1) control; (2) cisplatin (7?mg/kg body weight, intraperitoneal as a single dose); (3) curcumin (100?mg/kg via gavage, for 10 days); and (4) cisplatin and curcumin. The cisplatin-treated rats exhibited kidney injury manifested by increased serum urea and creatinine (p?<?0.05). The kidney tissue from the cisplatin treated rats also exhibited a significant increase in the malondialdehyde (MDA) levels (p?<?0.05). The treatment with curcumin prevented a rise in the serum urea, creatinine and MDA levels when compared to the control group kidneys (p?<?0.05). The analysis the nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin (SIRT) proteins (SIRT1, SIRT3 and SIRT4), which play important roles in the resistance to stress and the modulation of the threshold of cell death, showed similar trends (p?<?0.05). In the cisplatin-only treated rats, the induced renal injury decreased the levels of the NAMPT and SIRT proteins. Conversely, the curcumin increased the levels of the NAMPT and SIRT proteins in the cisplatin-treated rats (p?<?0.05). These data suggest that curcumin can potentially be used to reduce chemotherapy-induced nephrotoxicity, thereby enhancing the therapeutic window of cisplatin.     

Lessons learned from ischemic and cisplatin-induced nephrotoxicity in animals.

Following ischemic or nephrotoxic injury, the regenerating kidney assumes an earlier developmental stage and a less mature phenotype. Recovery involves the activation of a group of genes, including protooncogenes and growth factor genes that initiate and sustain cell growth. Inflammation also plays an important role in the recovery process as several of the changes in gene expression implicate the participation of the inflammatory cascade. Many of the changes in gene expression may eventually be reflected in the urine of the damaged kidney. By exploiting these changes in urine composition as a consequence of injury it should be possible to detect evidence of biologic effects of exposure and may yield predictions of eventual risk of serious damage to kidney.     

Protective effect of pomegranate seed oil against cisplatin-induced nephrotoxicity in rat

Abstract

Purpose: Clinical use of cisplatin is limited by its nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to kidney dysfunction. The aim of this study was to investigate the effect of pomegranate seed oil against nephrotoxicity induced by cisplatin in adult rats. Methods: Animals were divided into four groups. Group I received corn oil (1?mL/kg). Group II received cisplatin (8?mg/kg). Group III and IV received pomegranate seed oil (PSO) 0.4?mL/kg and 0.8?mL/kg one hour before cisplatin injection for 3 days, respectively. Blood samples were collected by cardiac puncture and used for measuring urea and creatinine concentration. Twenty-hour urine samples were collected to measure protein and glucose concentration. The right kidney fixed in formalin for histological examination and the left kidney was homogenized for measurement of malondialdehyde and total sulfhydryl groups. Results: A significant elevation of serum creatinine, urea, urinary glucose, protein concentrations, and non-significant decrease in total thiol content and increase in MDA level in kidney homogenates were observed in cisplatin-treated rats. Also cisplatin reduced animal’s body weight. Mild-to-moderate tubular cell necrosis, hyaline casts, and vascular congestion were observed in group II. PSO pre-treatment significantly decreased urinary protein, glucose, and serum creatinine concentration. PSO also caused a decrease in serum urea, renal MDA, and increase in thiol content, but the level of these parameters were not significant. Conclusion: The present results suggest that PSO is an effective agent for the prevention of cisplatin-induced renal dysfunction and oxidative damage in rat.     

Experimental study on effects of deferoxamine mesilate in ameliorating cisplatin-induced nephrotoxicity

Purpose: Cisplatin (CCDP), an indispensable agent of several chemotherapy protocols, has serious dose limiting side effects, including nephrotoxicity. In this experimental study, we used deferoxamine mesilate (DFO), an iron chelating agent, to ameliorate cisplatin-induced nephrotoxicity. Materials and methods: Sixty adult male bulb-c mice were divided in 6 equal groups. Group 1 received distilled water, group 2 received 100 mg/kg DFO, group 3 received 0.9 mg/kg CCDP, group 4 received 100 mg/kg DFO one hour before 0.9 mg/kg CCDP, group 5 received 1.8 mg/kg CCDP, and group 6 received 200 mg/kg DFO one hour before 1.8 mg/kg CCDP transperitoneally for 10 days. The next day, blood and urine samples were obtained, and all the animals were sacrificed, the kidneys and testes were removed, and histopathologic and biochemical analyses were performed. Results: Low-dose and high-dose CCDP treated mice had significantly more extensive proximal tubular degeneration (p < 0.001) when compared to control animals. Moreover, these changes were significantly less extensive in the mice taking DFO than mice taking CCDP. DFO showed no effect on cisplatin induced testicular histopathology. The cisplatin administration significantly increased the serum urea and plasma creatinin concentrations, and DFO administration prior to CCDP significantly decreased serum urea and plasma creatinin concentrations. Conclusion: Our findings suggest that DFO administration may be safe and useful for ameliorating cisplatin-induced nephrotoxicity.     

Potential of morin and hesperidin in the prevention of cisplatin-induced nephrotoxicity

Oxidative stress is one of the important mechanisms of cisplatin-induced nephrotoxicity. Therefore, this study was designed to explore the potential protective effects of morin and/or hesperidin on oxidative stress in cisplatin-induced nephrotoxicity. This study was performed on 42 Wistar rats. Rats were divided into seven groups: control, morin, hesperidin, cisplatin, cisplatin?+?morin, cisplatin?+?hesperidin, and cisplatin?+?morin?+?hesperidin. Morin and/or hesperidin were given for 10 consecutive days by oral gavage and on the 4th day a single dose of cisplatin (7?mg/kg) was injected intraperitoneally. After administrations, on the 11th day of the experiment the animals were killed, and malondialdehyde (MDA), nitric oxide (NOx), glutathione (GSH) levels and myeloperoxidase (MPO), catalase (CAT), superoxide dismutase (SOD) activity were measured. Cisplatin-treated rats showed increased levels of MDA, and decreased levels of NOx also activity of CAT. Morin and/or hesperidin pretreatment prevent oxidative stress in kidney tissue, while they increase the NOx level, CAT activity, and decrease MPO activity. In conclusion, morin?+?hesperidin pretreatment may have a significant potential for protection of cisplatin-induced nephrotoxicity.     

Effects of different doses of hyperbaric oxygen on cisplatin-induced nephrotoxicity

Cisplatin, an effective antineoplastic agent, frequently induces acute renal failure in animals and humans. Hyperbaric oxygen (HBO) has been shown to prevent cisplatin-induced nephrotoxicity in rats. This study investigated the effect of two different HBO regimes on renal functions, oxidative stress, and histopathological changes in rat kidneys after cisplatin treatment. Wistar rats were divided into five groups: control, HBO, cisplatin, cisplatin plus once daily HBO, and cisplatin plus twice daily HBO. Cisplatin was given as a single intraperitoneal dose of 6 mg/kg, and HBO was applied for 60 min at 2.5 atm for six days. HBO alone did not alter any biochemical parameters or histopathological findings compared with the control group. Cisplatin increased serum urea and creatinine levels and caused severe histopathological injury. In addition, cisplatin increased lipid peroxidation and impaired superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in kidney tissue. Once daily HBO after cisplatin treatment slightly reduced serum urea and creatinine levels and attenuated histopathological injury. HBO also reduced lipid peroxidation and increased SOD and GSH-Px activities significantly. Although twice daily HBO was determined to be more effective than once daily HBO on oxidative stress parameters, it increased serum creatinine levels and histopathological injury compared with the cisplatin group. It was concluded that HBO alone does not induce nephrotoxicity and oxidative stress in rat kidneys; once daily HBO may prevent cisplatin-induced nephrotoxicity, an effect that is partially mediated by the modification of oxidant/antioxidant systems in the kidneys; and twice daily HBO potentiates cisplatin nephrotoxicity by a ROS-independent mechanism.     

Curcumin counteracts cisplatin-induced nephrotoxicity by preventing renal tubular cell apoptosis

Curcumin has several biological functions particularly antioxidant and anti-inflammatory. The aims of this study are determination of the protective effects of curcumin on cisplatin-induced renal tubular cell apoptosis and related pathways in kidney. Eighteen male Wistar albino rats were randomly divided into three groups (n?=?6): the control, cisplatin (CP), and cisplatin?+?curcumin (CP?+?CUR). Acute renal damage was induced by single dose of cisplatin (7.5?mg/kg) injected by intraperitoneally (i.p). The animals of curcumin-treated group were received daily 200?mg/kg curcumin per os (po), starting from 2 days before the injection of cisplatin to the day of sacrifice. Forty-eight hours after cisplatin injection, samples of cardiac blood and kidneys were harvested from the animals. In this study, the major finding is that curcumin treatment ameliorates the following conditions associated with cisplatin-induced nephrotoxicity: (1) the development of kidney injury (histopathology), (2) inflammatory responses [myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, IL-10 levels], (3) the degree of lipid peroxidation [malondialdehyde (MDA) level], (4) renal tubular cell apoptosis (active caspase-3) and expression of related proteins [p53, Fas, and Fas ligand (Fas-L)] by immunohistochemistry, (5) renal dysfunction (serum urea and creatinine). In a conclusion, this study suggests that curcumin has antiapoptotic effect against cisplatin nephrotoxicity, in addition to anti-inflammatory and antioxidant properties.     

Whortleberry protects kidney against the cisplatin-induced nephrotoxicity: an experimental study

Purpose: This study investigated the antioxidant effects of whortleberry against cisplatin-induced nephrotoxicity in rats.

Material and methods: This study included 48 female Sprague–Dawley rats weighing 263.68?±?8.29?g. The rats were divided into the following six groups, with eight rats in each group: control, ethanol control, whortleberry control, cisplatin control, 16?mg/kg cisplatin +100?mg/kg whortleberry, and 16?mg/kg cisplatin +200?mg/kg whortleberry groups. Biochemical analysis was performed by measuring total oxidant status and total antioxidant status, histopathological analysis was performed by calculating proximal and distal tubule areas (μm²), and immunohistochemical analysis was performed by determining anti-Caspase-3 immunostaining. Differences among the groups were examined using one-way analysis of variance, and p?Results: Cisplatin treatment decreased the total antioxidant status and increased the total oxidant status and Caspase-3 level. Moreover, it resulted in the dilatation, vacuolization and loss of tubular epithelial cells; and glomerular degeneration and edema in the kidney tissues (p?p?Conclusions: Our results indicate that the antioxidant effects of the whortleberry decrease cisplatin-associated nephrotoxicity.     

Calcium channel blockers and prostate cancer

The relationship between calcium channel blockers and prostate cancer has been an area of increased interest to investigators. Calcium channel blockers have been shown to influence cell proliferation, differentiation, and apoptosis. Clinically, the association between calcium channel blockers and the development of prostate cancer has been controversial. However, on a basic science level, there is evidence that calcium channel blockers induce cytotoxicity in androgen receptor positive cell lines and may offer an innovative strategy for the treatment of castration-resistant prostate cancer.     

Cyclosporine nephrotoxicity in spontaneously hypertensive rats

In the present study, we investigated the combined, nephrotoxic effects of cyclosporine (CsA) and hypertension in young, spontaneously hypertensive rats (SHR). After 4 weeks of CsA therapy, SHR, compared with oil-treated SHR, showed an acceleration in the development of hypertension, mild renal insufficiency, and the accumulation of periodic-acid-Schiff-positive (PAS [+]) material in periglomerular arterioles. By electron microscopy, PAS(+) material was composed of intracytoplasmic inclusion bodies consistent with the accumulation of renin granules. This finding was demonstrated in SHR after 4 weeks of CsA therapy but not after 8 weeks of therapy. By contrast, CsA had no significant effect on blood pressure in Wistar-Kyoto rats, a normo-tensive control. To investigate the effect of unilateral nephrectomy (UNx) on the development of renal histopathologic changes in this model, SHR were subjected to uninephrectomy and CsA or oil therapy. UNx accelerated the development of hypertension in all SHR groups. SHR subjected to UNx demonstrated no renal histopathologic changes after CsA or oil treatment. In conclusion, CsA accelerates the development of hypertension in SHR, and this effect is probably renin-mediated. The combination of UNx and CsA therapy in the SHR does not result in significant renal histologic damage.