Nephrotoxicity In Experimental Animals Research Articles

Effects of Microplastic (MP) Exposure at Environmentally Relevant Doses on the Structure, Function, and Transcriptome of the Kidney in Mice.

As a common emerging environmental pollutant, microplastics (MPs) have been detected in a variety of environmental media and human bodies. The potential toxic effects and mechanisms of MPs need to be revealed urgently. MPs can be deposited in the kidney, and exposure to high doses of MPs can cause nephrotoxicity in experimental animals. In this study, we investigated the effects of exposure to polystyrene microplastics (PS-MPs) at environmentally relevant doses (0.1 and 1 mg/L) on kidney structure, function, and transcriptome in mice. We found that mice exposed to PS-MPs in drinking water for eight weeks had no change in body weight or kidney coefficient. PS-MPs administration decreased the levels of blood urea nitrogen (BUN) in mice, while serum creatinine (CRE) and uric acid (UA) concentrations were unaffected. Through using periodic acid-Schiff (PAS) and Masson staining, we discovered that the glomerular tuft area increased in the PS-MP-treated mice, while the degree of renal fibrosis remained unchanged. Furthermore, renal cortex transcriptomic analysis identified 388 and 303 differentially expressed genes (DEGs) in the 0.1 and 1 mg/L dose groups, respectively. The DEGs were highly enriched in mitochondrial-related terms and pathways of thermogenesis and oxidative phosphorylation. Moreover, protein-protein interaction (PPI) network analysis revealed that cytochrome b-c1 complex subunit 10 (UQCR11) and cytochrome c oxidase subunit 3 (MT-CO3) were important node proteins. These findings suggest that environmental exposure to MPs can cause abnormalities in renal structure and filtration function and that long-term exposure to MPs may be a risk factor for renal disease.

Protective effect of dapagliflozin on colistin-induced renal toxicity

Objectives: Multiple-drug resistance to Gram-negative bacteria has increased signifi-cantly in recent years. Colistin is increasingly used as a last line of defense against these bacteria. However, colistin has been associated with nephrotoxicity in experimental animals. This study explores the protective effect of dapagliflozin in a rodent model of nephrotoxicity. Material Method: The present study includes a total of 24 male rats, of which 16 were given a single 20 mg/kg dose of colistin (Colimycin 150 mg/mL) intravenously to induce renal toxicity. The remaining eight rats were given no drugs in order to serve as the control, Group A. The 16 rats treated with colistin were then divided into two groups. Rats in Group B received 0.9% NaCl saline solution at a dose of 30 mL/kg/day intraperitoneally (i.p.) and 10 mg/kg/day dapagliflozin (Forziga 10 mg) via oral gavage. Those in Group C received 0.9% NaCl saline solution at an i.p. dose of 30 mL/kg/day. Both saline and dapagliflozin were administered as described over the course of ten days. The animals were euthanized and blood samples were taken by cardiac puncture for further analysis. Their kidneys were removed for histopathological and biochemical examination. Results: Levels of creatinine, BUN, KIM-1, and MDA were significantly increased in the 16-rat (Groups B and C) treatment group, in comparison to the control group; however, these biomarkers were significantly normalized in Group B, which had received dapagliflozin in addition to saline. The GSH levels of Group C showed significant decline when compared to those of the control group, and were significantly normalized in Group B. Histologically, in Group 2, we observed severe tubular dilatation and tubular epithelial cell injury in comparison to the control group. These severe anatomical changes were decreased in Group B. Conclusion: Apart from its positive effect on glucose regulation, which is the usual purpose of dapagliflozin, we observed that in colistin-induced nephrotoxicity, it decreases oxidative stress by inhibiting SGLT-2, and has restorative effects in terms of histopathology and biochemistry. These findings offer hope that the use of dapagliflozin may be protective for contrast nephropathy, which causes renal tubule damage through oxidative mechanisms. Future studies will further clarify the mechanistic action of colistin and dapagliflozin, and may support the hypothesis that dapagliflozin can be used as an adjunctive therapy in all nephrotoxic conditions.

Renoprotective Effects of Valsartan And Amlodipine in a Nephrotoxic Model of Experimental Animals

Background: Calcium channel blockers and AT1 antagonists have efficacious effects to control elevated blood pressure by different mechanisms. They are used widely in co-morbid hypertensive patients either to prevent deterioration of blood pressure or to protect the cardiovascular diseases from further progression. Objectives: This work aims to investigate the protective effects of valsartan and amlodipine against gentamicin-induced nephrotoxicity in experimental animals. Methods: Twenty-four rabbits were divided randomly into four groups, each of six animals. The first group was kept as the normal control group. Second, third and fourth groups were taken as a nephrotoxic model by giving gentamicin (80mg/kg IP) for 7 days. Blood samples were collected to investigate the kidney biomarkers including serum creatinine, BUN, Crcl, uric acid and potassium level. Urine collection was done to measure pH, volume as well as urine creatinine. Bodyweight was measured before and after treatment, furthermore, the weights of heart and kidneys were done at the end of the study. Results: The outcomes of this study showed a significant elevation in all kidney biomarkers in a nephrotoxic-induced group accompanied by the reduction in the weights of heart and kidney as compared with the control one. The treated groups either valsartan or amlodipine showed little improvements in some parameters compared with the nephrotoxic-induced group. Conclusion: From the results of the present study, it was suggested that both medications might have renoprotective effects that obviously reduced the kidney biomarkers as well as there was no significant difference between the two drugs concerning their protective effect.

Pithecellobium dulce fruit extract mitigates cyclophosphamide-mediated toxicity by regulating proinflammatory cytokines.

Pithecellobium dulce (Family: Fabaceae) is an edible fruit widely used in Asian-Pacific region. In the present study, we had investigated the protective effect of P. dulce fruit extract in mitigating harmful effects of the chemotherapeutic drug, cyclophosphamide (CTX). Our results showed that P. dulce treatment could significantly (p<.01) overcome CTX-induced immunosuppression accompanied with urotoxicity, hepatotoxicity, and nephrotoxicity in experimental animals. This was supported by histopathological data which proved that toxic effects of CTX in urinary bladder walls, liver, and kidney were markedly inhibited with P. dulce administration. Further, we observed significant alterations in in situ formation or release of granulocyte-macrophage colony-stimulation factor (GM-CSF) and interferon gamma (IFN ɤ) in the P. dulce treated group compared with cyclophosphamide control group. The outcome of the study could have wide range of applications in combating chemotherapy-associated malnutrition as well as in cancer drug development. PRACTICAL APPLICATIONS: CTX is a commonly used broad spectrum chemotherapeutic drug with severe side effects including immune suppression, malnutrition, urotoxicity, and nephrotoxicity. Identification of a novel immunomodulator from natural sources can resolve these side effects and could improve the quality of life of cancer patients receiving CTX as chemotherapeutic drug. In the present study, we had proved that P. dulce administration could significantly reduce CTX-induced immunotoxicity, urothelial toxicity, and nephrotoxicity. Administration of P. dulce showed a pronounced improvement in total leukocyte count, bone marrow cellularity/α-esterase activity, expression of antioxidant glutathione and cytokines (GM-CSF and INF-ɤ) compared to CTX-treated mice group. Further, histopathological analysis confirmed the protective efficacy of P. dulce against CTX-induced urothelial, hepato and kidney damage. These insights are fostering new combinational therapeutic approaches to cancer treatment.

Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties

Silymarin (SLY) and naringin (NRG) are natural flavonoids that have been reported to have many benefits and medicinal properties. The present study was designed to investigate the protective effect of SLY and NRG against methotrexate (MTX)-induced nephrotoxicity in experimental animals. Rats were subjected to oral pretreatment of SLY (25 and 50 mg/kg body weight (b.w.)/day) and NRG (50 and 100 mg/kg b.w./day) for 7 days against renal toxicity induced by single intraperitoneal administration of MTX (20 mg/kg b.w.). MTX resulted in an increase in serum toxicity markers, lipid peroxidation, and reduction in activities of antioxidant enzymes. Additionally, MTX provoked inflammatory responses by increasing the levels of TNF-α, IL-1β, IL-6, NF-κB, and activation of COX-2 and iNOS. Furthermore, MTX administration caused apoptosis and autophagy by increasing activity of Caspase-3 and light chain 3B level. Conversely, SLY and NRG therapy significantly decreased these values in rats. This study demonstrated that SLY and NRG protect against MTX-induced nephrotoxicity. Practical applications Chemotherapeutic drugs have been used for cancer treatment for many years. However, in the treatment process, they may damage organs such as liver and kidney, prolong the treatment process and negatively affects patient welfare. This study revealed that silymarin and naringin exhibited potent anti-inflammatory, antiapoptotic, and antiautophagic effect in renal injury caused by methotrexate, a chemotherapeutic drug. Therefore, treatment silymarin and naringin can be used for the beneficial effect against methotrexate-induced kidney damage in cancer chemotherapy.

Nephroprotective Potential of Alstonia scholaris in Cisplatin Induced Nephrotoxicity in Experimental Animals

The present investigation was aimed to determine the alterations in antioxidant, biochemical and histopathological parameters in cisplatin (cDDP) induced nephrotoxicity and its protection by treatments with aqueous and ethanolic leaf extracts of Alstonia scholaris. Acute nephrotoxicity was induced by single intra-peritoneal administration of cDDP (12 mg kg−1) in wistar rats. Nephrotoxic rats were treated with quercetin (50 mg kg−1), aqueous and ethanolic leaf extracts (300 mg kg−1) by oral gavage. Cisplatin treatment elevated (P 0.05) creatinine, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Leaf extracts administration also reduced (P < 0.05) erythrocyte and renal MDA levels following cDDP treatment. The restorations of various antioxidant and renal parameters were also supported by the histopathological findings of renal tissue. Administrations with ethanolic leaf extract have high potential to minimize cDDP induced renal damage as indicated by restoration of biochemical, antioxidant and histopathological alterations in nephrotoxic rats as compared to aqueous extract of A. scholaris.

1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats

BackgroundCisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals. MethodsAnimals were divided into four groups of six mice each. Group A: normal control, vehicle (1 % (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5mg/kg). Group C: 1,2-diazole (10mg/kg) + cisplatin and Group D: silymarin (50mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses. ResultsPretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2-diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity. ConclusionThese analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity.

Sunitinib improves chemotherapeutic efficacy and ameliorates cisplatin-induced nephrotoxicity in experimental animals

Therapeutic inhibition of angiogenesis has a benefit in the treatment of neoplastic diseases. Cisplatin is a widely used anti-cancer agent; however, it has serious side effects on non-tumor cells and causes nephrotoxicity due to its reactive oxygen species-mediated effect. Thus, a combination between cisplatin and angiogenesis inhibitors may be useful in cancer treatment. In the present study, the effect of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, on the antitumor activity as well as the nephrotoxic side effect of cisplatin was examined. The antitumor activity was evaluated both in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo using a mouse model of solid tumor. In addition, the effect of cisplatin and/or sunitinib on the angiogenic marker, VEGF, was examined. Nephrotoxicity was induced in rats by single i.p. injection of cisplatin (6 mg/kg). Sunitinib significantly potentiated the cytotoxic effect of cisplatin in vitro and in vivo. The nephrotoxicity of cisplatin was evidenced by decrease in the body weight, increase in kidney/body weight ratio and decrease in the percent survival of rats. The toxicity was also confirmed biochemically by measuring some kidney function parameters and oxidative stress markers. Sunitinib significantly decreased cisplatin-induced changes in serum creatinine, blood urea nitrogen, creatinine clearance and micro total protein in urine, renal malondialdehyde levels and reduced glutathione contents. In addition, sunitinib effectively blunted cisplatin-induced proximal and distal tubules necrosis. The potential for sunitinib to ameliorate the cisplatin-evoked toxicity as well as to improve the chemotherapeutic effect could have beneficial implications for patients undergoing chemotherapy with cisplatin.

Protective Effect of KCl Loading in Gentamicin Nephrotoxicity

Aminoglycoside nephrotoxicity in experimental animals can be reduced by calcium loading, inducing diabetes, and giving thyroid hormone, while a potassium deficient diet enhances aminoglycoside nephrotoxicity. This study investigated whether potassium loading protects against gentamicin nephrotoxicity in the rat. In part I, group GK ate a diet containing 3.5% potassium and drank 0.2 mol/L KCl. Pair-fed rats eating a standard diet, group G, ate a 1% potassium diet and drank water. After 10 days, each group received gentamicin subcutaneously, 60 mg/kg twice daily for 8 days. The control groups, K and C, received the high or normal potassium diet, respectively. To control for a protective effect from a high solute load, the effect of equimolar NaCl loading was studied in group GNa and Na. At the end of the 8 days of gentamicin, inulin clearance was significantly higher in GK compared with G(0.6 +/- 0.1 v 0.3 +/- 0.1 mL/min per 100 g body weight [BW], P less than 0.05), but group GNa (0.4 +/- 0.1 mL/min per 100 g BW) was not different from group G. Morphological studies demonstrated that potassium-loaded rats (group GK) had significantly less proximal tubular necrosis compared with rats on a standard potassium diet, group G. Sodium loading did not protect against cellular necrosis. Part II studied renal function, cortical Na,K-adenosine triphosphatase (ATPase) and gentamicin accumulation after 2 days of gentamicin to determine the early functional and biochemical effects of potassium loading before overt renal functional impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I study of weekly-administered iproplatin [cis-dichloro-trans-dihydroxy-bis-isopropylamine platin (chip, JM9)

Iproplatin [cis-dichlor-trans-dihydroxy-bis-isopropylamine platinum (CHIP, JM9)] is a new antineoplastic platinum analogue with an octahedral conformation. It has more water solubility than does cisplatin and was found to have less neurotoxicity and nephrotoxicity in experimental animals than cisplatin. Like cisplatin, it has been demonstrated to have a broad spectrum of activity in experimental tumor systems. A phase I study of iproplatin was conducted in 28 patients (12 with melanoma, 8 with sarcoma, 6 with breast cancer, and 2 with colon cancer). All patients had failed prior chemotherapy. Four consecutive doses of iproplatin were administered at weekly intervals followed by a rest period of two weeks for hematologic recovery (one course). One hundred forty-two weekly doses were administered with all patients except three receiving at least one full course. The weekly starting dose of 40 mg/m2 was increased to 120 mg/m2 given over 30 minutes without hydration. Myelosuppression predominantly thrombocytopenia, was the dose-limiting toxicity at weekly doses of greater than or equal to 95 mg/m2 per course. With iproplatin doses 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median granulocyte counts were 2.6 x 10(3)/mm3, 2.2 x 10(3)/mm3, and 1.8 x 10(3)/mm3, respectively. Similarly, at iproplatin doses of 75 mg/m2, 95 mg/m2, and 120 mg/m2, the lowest median platelet counts were 144 x 10(3)/mm3, 99 x 10(3)/mm3, and 31 x 10(3)/mm3, respectively. Mild to moderate nausea and vomiting were observed in the majority of patients. No significant neurotoxicity, nephrotoxicity, or ototoxicity was observed. Objective tumor regression was not observed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)