Abstract
Imatinib is a tyrosine kinase inhibitor widely administered against chronic myeloid leukemia. On the other hand, drug-induced kidney proximal tubular injury, electrolytes disturbances, and renal failure is a clinical complication associated with imatinib therapy. There is no precise cellular mechanism(s) for imatinib-induced renal injury. The current investigation aimed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of imatinib nephrotoxicity. Rats received imatinib (50 and 100 mg/kg, oral, 14 consecutive days). Serum and urine biomarkers of renal injury and markers of oxidative stress in the kidney tissue were assessed. Moreover, kidney mitochondria were isolated, and mitochondrial indices, including mitochondrial depolarization, dehydrogenases activity, mitochondrial permeabilization, lipid peroxidation (LPO), mitochondrial glutathione levels, and ATP content were determined. A significant increase in serum (Creatinine; Cr and blood urea nitrogen; BUN) and urine (Glucose, protein, gamma-glutamyl transferase; γ-GT, and alkaline phosphatase; ALP) biomarkers of renal injury, as well as serum electrolytes disturbances (hypokalemia and hypophosphatemia), were evident in imatinib-treated animals. On the other hand, imatinib (100 mg/kg) caused an increase in kidney ROS and LPO. Renal tubular interstitial nephritis, tissue necrosis, and atrophy were evident as tissue histopathological changes in imatinib-treated rats. Mitochondrial parameters were also adversely affected by imatinib administration. These data represent mitochondrial impairment, renal tissue energy crisis, and oxidative stress as possible mechanisms involved in the pathogenesis of imatinib-induced renal injury and serum electrolytes disturbances.
Highlights
Tyrosine kinase inhibitors are widely administered against chronic myeloid leukemia in human
Imatinib is clinically administered against chronic myeloid leukemia and metastatic gastrointestinal stromal tumors (Cismowski 2007a, 2007b)
The data obtained from the current investigation mention the potential role of mitochondrial injury and oxidative stress in the pathogenesis of imatinib-induced nephrotoxicity and serum electrolytes imbalance
Summary
Tyrosine kinase inhibitors are widely administered against chronic myeloid leukemia in human. These drugs had a revolutionary effect on the management of malignancies in patients, several adverse reactions have been associated with their clinical use (Cismowski 2007a, 2007b). Imatinib is a tyrosine kinase inhibitor clinically applied against leukemia and metastatic gastrointestinal stromal tumors (Cismowski, 2007a). Nausea, vomiting, abdominal pain, and elevated serum transaminase level are associated with imatinib therapy (Cismowski, 2007a; Francis et al, 2015; Cross et al, 2006; Tonyali et al, 2010). Nephrotoxicity and acute renal failure might accompany imatinib administration (Cismowski, 2007a). There is no precise mechanism for imatinib-induced renal injury
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