Mohammad Mehdi Ommati1, Omid Farshad2, Vahid Ghanbarinejad2, Hamid Reza Mohammadi2,3, Mousavi Khadijeh2, Azarpira Negar, Mahboubi Zahra2, Farshid Ilkhaninasab2, Leila Moezi2,4, Reza Heidari2.
Abstract
BACKGROUND: Ifosfamide (IFO) is an alkylating agent administered against different types of malignancies. Several cases of renal injury and serum electrolytes disturbances have been reported in IFO-treated patients. Oxidative stress and mitochondrial dysfunction are suspected of being involved in the mechanism of IFO nephrotoxicity. Carnosine is a dipeptide which its antioxidant and mitochondria protecting properties have been mentioned in different experimental models. The current study aimed to evaluate the nephroprotective properties of carnosine against IFO-induced renal injury.
METHODS: Rats were treated with IFO (50 mg/kg, i.p) alone or in combination with carnosine. Serum and urine biomarkers of renal injury in addition to kidney markers of oxidative stress were evaluated. Moreover, kidney mitochondria were isolated, and some mitochondrial indices were assessed.
RESULTS: Elevated serum creatinine and BUN, hypokalemia, and hypophosphatemia, in addition, to an increase in urine glucose, protein, γ-GT, and alkaline phosphatase (ALP), were evident in IFO-treated animals. IFO also caused an increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH levels and antioxidant capacity were also depleted with IFO therapy. Mitochondrial dehydrogenase activity, GSH level, membrane potential, and ATP content were decreased while mitochondrial LPO and permeabilization were increased in IFO group. Carnosine (250 and 500 mg/kg, i.p) mitigated IFO-induced oxidative stress and mitochondrial impairment in renal tissue.
CONCLUSION: Our data suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by IFO. On the other hand, carnosine supplementation protected kidneys against IFO-induced injury through regulating mitochondrial function and mitigating oxidative stress. © Georg Thieme Verlag KG Stuttgart · New York.
BACKGROUND: Ifosfamide (IFO) is an alkylating agent administered against different types of malignancies. Several cases of renal injury and serum electrolytes disturbances have been reported in IFO-treated patients. Oxidative stress and mitochondrial dysfunction are suspected of being involved in the mechanism of IFO nephrotoxicity. Carnosine is a dipeptide which its antioxidant and mitochondria protecting properties have been mentioned in different experimental models. The current study aimed to evaluate the nephroprotective properties of carnosine against IFO-induced renal injury.
METHODS: Rats were treated with IFO (50 mg/kg, i.p) alone or in combination with carnosine. Serum and urine biomarkers of renal injury in addition to kidney markers of oxidative stress were evaluated. Moreover, kidney mitochondria were isolated, and some mitochondrial indices were assessed.
RESULTS: Elevated serum creatinine and BUN, hypokalemia, and hypophosphatemia, in addition, to an increase in urine glucose, protein, γ-GT, and alkaline phosphatase (ALP), were evident in IFO-treated animals. IFO also caused an increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH levels and antioxidant capacity were also depleted with IFO therapy. Mitochondrial dehydrogenase activity, GSH level, membrane potential, and ATP content were decreased while mitochondrial LPO and permeabilization were increased in IFO group. Carnosine (250 and 500 mg/kg, i.p) mitigated IFO-induced oxidative stress and mitochondrial impairment in renal tissue.
CONCLUSION: Our data suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by IFO. On the other hand, carnosine supplementation protected kidneys against IFO-induced injury through regulating mitochondrial function and mitigating oxidative stress. © Georg Thieme Verlag KG Stuttgart · New York.
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Year: 2019
PMID： 31671464 DOI： 10.1055/a-1017-5085
Source DB: PubMed Journal: Drug Res (Stuttg) ISSN： 2194-9379