The potential role of mitochondrial impairment in the pathogenesis of imatinib-induced renal injury

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.

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

“…Calcium antagonists [251][252][253][254][255] and ACE-inhibitors [256][257][258][259][260] reduced respiration and ATP synthesis. Sorafenib directly impaired mitochondrial function at clinically relevant concentrations [261] whereas imatinib lacked direct mitochondrial effects but affected mitochondrial functions via altered kinase and other signalling pathways [261,262]. Likewise, ciclosporin A, rapamycin, and tacrolimus did not directly induce mitochondrial dysfunction but decreased energy production [263,264].…”

Taurine mitigates cirrhosis-associated heart injury through mitochondrial-dependent and antioxidative mechanisms

“…A luciferase-luciferin-based kit (Enliten, Promega, Madison, WI) was used to measure mitochondrial ATP content [ 82 , 83 ]. Samples and buffer solutions were prepared based on the kit instructions.…”

“…Briefly, 500 µl of mitochondrial samples (1 mg protein/ml) were treated with 100 µl of ice-cooled TCA solution (0.5% w/v in double-distilled water) and centrifuged (15,000 g, 15 min, 4°C). Afterward, 100 µl of ATP kit content was added to 100 µl of the supernatant (in the dark), and the luminescence intensity of samples was measured (λ = 560 nm using a FLUOstar Omega multifunctional microplate reader, BMG Labtech Inc., Germany) [ 83 ].…”

The effect of imatinib administered in the prenatal period on testis development in rats

“…A number of studies have also shown that imatinib increases oxidative stress levels. 35,36 Based on our biochemical findings, although oxidative stress increased significantly in testis tissue in the Imatinib-20 group compared to the control group at TBARS measurements, we determined a decrease in the Imatinib-60 group. One study involving an induced hepatic fibrosis model reported a decrease in oxidative stress in a group receiving imatinib.…”