The Nephroprotective Role of Carnosine Against Ifosfamide-Induced Renal Injury and Electrolytes Imbalance is Mediated Via the Regulation of Mitochondrial Function and Alleviation of Oxidative StressAcknowledgments This investigation was financially supported by the Vice Chancellor of Research Affairs of Shiraz University of Medical Sciences (Grant # 95–01–36–13619). Authors thank Pharmaceutical Sciences Research Center (PSRC) of Shiraz University of Medical Sciences for providing technical facilities to carry out this study.
received 07. April 2019
accepted 19. September 2019
31. Oktober 2019 (online)
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.
Key wordsantioxidants/NO pathways drugs - biomarkers - endocrine pharmacology - toxicology - adverse drug reactions - pharmacology - drug metabolism - apoptosis - gastrointestinal pharmacology - non-specific cation channels - experimental pharmacology - cardiovascular pharmacology - cellular signal transduction by receptors and ion channels - renal pharmacology - biologics - peptide - energy metabolism - Fanconi syndrome - mitochondria - nephrotoxicity - oxidative stress
* The authors contributed equally to this work.
- 1 Sahni V, Choudhury D, Ahmed Z. Chemotherapy-associated renal dysfunction. Nature Reviews Nephrology 2009; 5: 450
- 2 Rider BJ. Ifosfamide. xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier; 2007. p 1-4
- 3 Oberlin O, Fawaz O, Rey A. et al. Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 2009; 27: 5350-5355
- 4 Leem AY, Kim HS, Yoo BW. et al. Ifosfamide-induced Fanconi syndrome with diabetes insipidus. The Korean Journal of Internal Medicine 2014; 29: 246-249
- 5 Berns JS, Haghighat A, Staddon A. et al. Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients. Cancer 1995; 76: 497-500
- 6 Zhang J, Lu H. Ifosfamide induces acute renal failure via inhibition of the thioredoxin reductase activity. Free Radical Biol Med 2007; 43: 1574-1583
- 7 Sener G, Sehirli Ö, Yegen BÇ. et al. Melatonin attenuates ifosfamide-induced Fanconi syndrome in rats. J Pineal Res 2004; 37: 17-25
- 8 Şehirli Ö, Şakarcan A, Velioğlu-Öğünç A. et al. Resveratrol improves ifosfamide-induced Fanconi syndrome in rats. Toxicol Appl Pharmacol 2007; 222: 33-41
- 9 Hall AM, Bass P, Unwin RJ. Drug-induced renal Fanconi syndrome. QJM 2014; 107: 261-269
- 10 Shaik ZP, Fifer EK, Nowak G. Akt activation improves oxidative phosphorylation in renal proximal tubular cells following nephrotoxicant injury. American Journal of Physiology - Renal Physiology 2008; 294: F423-F432
- 11 Servais H, Ortiz A, Devuyst O. et al. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation. Apoptosis 2008; 13: 11-32
- 12 Nissim I, Horyn O, Daikhin Y. et al. Ifosfamide-induced nephrotoxicity: Mechanism and prevention. Cancer Res 2006; 66: 7824-7831
- 13 Budzeń S, Rymaszewska J. The biological role of carnosine and its possible applications in medicine. Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University 2013; 22: 739-744
- 14 Ouyang L, Tian Y, Bao Y. et al. Carnosine decreased neuronal cell death through targeting glutamate system and astrocyte mitochondrial bioenergetics in cultured neuron/astrocyte exposed to OGD/recovery. Brain Res Bull 2016; 124: 76-84
- 15 Zheng Z, Schmidt-Ott KM, Chua S. et al. A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse. Proc Natl Acad Sci USA 2005; 102: 2502-2507
- 16 Heidari R, Jafari F, Khodaei F. et al. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology 2018; 23: 351-361
- 17 Meeks RG, Harrison S. Hepatotoxicology. CRC Press; 1991: 716 p
- 18 Truong DH, Eghbal MA, Hindmarsh W. et al. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab Rev 2006; 38: 733-744
- 19 Ahmadian E, Khosroushahi AY, Eghbal MA. et al. Betanin reduces organophosphate induced cytotoxicity in primary hepatocyte via an anti-oxidative and mitochondrial dependent pathway. Pestic Biochem Physiol 2018; 144: 71-78
- 20 Ahmadian E, Eftekhari A, Fard JK. et al. In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity. Arch Pharmacal Res 2017; 40: 1296-1313
- 21 Ommati MM, Heidari R, Jamshidzadeh A. et al. Dual effects of sulfasalazine on rat sperm characteristics, spermatogenesis, and steroidogenesis in two experimental models. Toxicol Lett 2018; 284: 46-55
- 22 Heidari R, Behnamrad S, Khodami Z. et al. The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother 2019; 109: 103-111
- 23 Heidari R, Niknahad H. The role and study of mitochondrial impairment and oxidative stress in cholestasis. In: Vinken M. editor Experimental Cholestasis Research. New York, NY: Springer New York; 2019. p 117-132
- 24 Rehman MU, Tahir M, Ali F. et al. Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: The protective effect of Ellagic acid. Mol Cell Biochem 2012; 365: 119-127
- 25 Berrak SG, Pearson M, Berberoğlu S. et al. High-dose ifosfamide in relapsed pediatric osteosarcoma: Therapeutic effects and renal toxicity. Pediatr Blood Cancer 2005; 44: 215-219
- 26 Stöhr W, Paulides M, Bielack S. et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: A report from the Late Effects Surveillance System. Pediatr Blood Cancer 2007; 48: 447-452
- 27 Zamlauskitucker MJ, Morris ME, Springate JE. Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol 1994; 129: 170-175
- 28 Springate JE. Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo. 1997 1997. Wiley Online Library p 75-79
- 29 Brookes PS, Yoon Y, Robotham JL. et al. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. American Journal of Physiology-Cell Physiology 2004; 287: C817-C833
- 30 Hipkiss AR. Chapter 3 Carnosine and Its Possible Roles in Nutrition and Health. In: Research BTAiF, Nutrition. editors Academic Press; 2009. p 87-154
- 31 Chakraborti S, Rahaman SM, Alam MN. et al. Na+/K+-ATPase: A Perspective. In: Chakraborti S, Dhalla NS. editors Regulation of Membrane Na+-K+ATPase. Springer International Publishing; 2016. p 3-30
- 32 Baek S-H, Noh AR, Kim K-A. et al. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke 2014; 45: 2438-2443
- 33 Heidari R, Abdoli N, Ommati MM. et al. Mitochondrial impairment induced by chenodeoxycholic acid: The protective effect of taurine and carnosine supplementation. Trends in Pharmaceutical Sciences 2018; 4: 99-108