Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

Abstract

Rivaroxaban as a small molecule is able to directly and reversibly inhibit the factor Xa. This study was designed to figure out the evaluation effect of rivaroxaban on mitochondria obtained from rat kidneys. We isolated mitochondria from rat kidneys using gradient centrifugation. Then, the toxicity parameters including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse and cytochrome c release were measured in kidneys mitochondria following the exposure to rivaroxaban. The results showed that rivaroxaban (1.4 and 2.8 mM) raised the reactive oxygen species (ROS) generation, swelling in the mitochondria, collapse in the mitochondrial membrane potential (MMP) and cytochrome c release in the mitochondria isolated from kidneys. While, rivaroxaban at a higher concentration of 5.6 mM showed the opposite effect compared to other lower concentrations. The results indicate that rivaroxaban may have antioxidant effects at high concentrations. The results suggest that rivaroxaban (5.6 mM) has protective effects against oxidative stress and mitochondrial toxicity.

Key words

Rivaroxaban - kidneys - mitochondria - ROS - antioxidant

• References

• 1 Ishimoto Y, Inagi R. Mitochondria: A therapeutic target in acute kidney injury. Nephrol Dial Transplant 2016; 31: 1062-1069
• 2 Marullo R, Werner E, Degtyareva N. et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One 2013; 8: e81162
• 3 Plotnikov EY, Kazachenko AV, Vyssokikh MY. et al. The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney Int 2007; 72: 1493-1502
• 4 Pourahmad J, Hosseini MJ. Application of isolated mitochondria in toxicological and clinical studies. Iran J Pharm Res 2012; 11: 703-704
• 5 Ding W, Guo H, Xu C. et al. Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury. Oncotarget 2016; 7: 17479-17491
• 6 Ratliff BB, Abdulmahdi W, Pawar R. et al. Oxidant mechanisms in renal injury and disease. Antioxid Redox Signal 2016; 25: 119-46
• 7 Fu PP, Xia Q, Hwang HM. et al. Mechanisms of nanotoxicity: Generation of reactive oxygen species. J Food Drug Anal 2014; 22: 64-75
• 8 Manke A, Wang L, Rojanasakul Y. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int 2013; 2013: 942916
• 9 Alvarez E, Paradela-Dobarro B, Raposeiras-Roubin S. et al. Protective, repairing and fibrinolytic effects of rivaroxaban on vascular endothelium. Br J Clin Pharmacol 2018; 84: 280-291
• 10 Kim PY, Yeh CH, Dale BJ. et al. Mechanistic basis for the differential effects of rivaroxaban and apixaban on global tests of coagulation. TH Open 2018; 2: e190-e201
• 11 Kvasnicka T, Malikova I, Zenahlikova Z. et al. Rivaroxaban – metabolism, pharmacologic properties and drug interactions. Curr Drug Metab 2017; 18: 636-642
• 12 Ofek F, Bar Chaim S, Kronenfeld N. et al. International normalized ratio is significantly elevated with rivaroxaban and apixaban drug therapies: A retrospective study. Clin Ther 2017; 39: 1003-1010
• 13 Burness CB, Perry CM. Rivaroxaban: A review of its use in the treatment of deep vein thrombosis or pulmonary embolism and the prevention of recurrent venous thromboembolism. Drugs 2014; 74: 243-262
• 14 Fattah TA, Saeed A. A review on the synthetic approaches of rivaroxaban: An anticoagulant drug. Tetrahedron: Asymmetry 2017; 28: 485-504
• 15 Jain N, Reilly RF. Clinical pharmacology of oral anticoagulants in patients with kidney disease. Clin J Am Soc Nephrol 2018; pii: CJN.02170218
• 16 Chan YH, Yeh YH, Hsieh MY. et al. The risk of acute kidney injury in Asians treated with apixaban, rivaroxaban, dabigatran, or warfarin for non-valvular atrial fibrillation: A nationwide cohort study in Taiwan. Int J Cardiol 2018; 265: 83-89
• 17 Lutz J, Jurk K, Schinzel H. Direct oral anticoagulants in patients with chronic kidney disease: Patient selection and special considerations. Int J Nephrol Renovasc Dis 2017; 10: 135-143
• 18 Muster H, Alcorn Jr. H. Rivaroxaban in chronic hemodialysis patients. Am J Nephrol 2016; 43: 227-228
• 19 Imano H, Kato R, Tanikawa S. et al. Factor Xa inhibition by rivaroxaban attenuates cardiac remodeling due to intermittent hypoxia. J Pharmacol Sci 2018; 137: 274-282
• 20 Ishibashi Y, Matsui T, Fukami K. et al. Rivaroxaban inhibits oxidative and inflammatory reactions in advanced glycation end product-exposed tubular cells by blocking thrombin/protease-activated receptor-2 system. Thromb Res 2015; 135: 770-773
• 21 Bukowska A, Zacharias I, Weinert S. et al. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol 2013; 71: 114-123
• 22 Salimi A, Roudkenar MH, Seydi E. et al. Chrysin as an anti-cancer agent exerts selective toxicity by directly inhibiting mitochondrial complex II and V in CLL B-lymphocytes. Cancer Investigation 2017; 35: 174-186
• 23 Shaki F, Hosseini MJ, Ghazi-Khansari M. et al. Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochim Biophys Acta 2012; 1820: 1940-1950
• 24 Zhao Y, Ye L, Liu H. et al. Vanadium compounds induced mitochondria permeability transition pore (PTP) opening related to oxidative stress. J Inorg Biochem 2010; 104: 371-378
• 25 Salimi A, Motallebi A, Ayatollahi M. et al. Selective toxicity of persian gulf sea cucumber holothuria parva on human chronic lymphocytic leukemia b lymphocytes by direct mitochondrial targeting. Environmental Toxicology 2017; 32: 1158-1169
• 26 Ewees MG, Messiha BAS, Abo-Saif AA. et al. Interference with coagulation cascade as a novel approach to counteract cisplatin-induced acute tubular necrosis; an experimental study in rats. Front Pharmacol 2018; 9: 1155
• 27 Siguret V, Abdoul J, Delavenne X et al. Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability. J Thromb Haemost 2019; (In Press).
• 28 Di Lullo L, Tripepi G, Ronco C. et al. Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: Real world data. J Nephrol 2018; 31: 751-756
• 29 Li B, Chen X, Yang W. et al. Single-walled carbon nanohorn aggregates promotes mitochondrial dysfunction-induced apoptosis in hepatoblastoma cells by targeting SIRT3. Int J Oncol 2018; 53: 1129-1137
• 30 Kim JS, Song KS, Yu IJ. Multiwall Carbon nanotube-induced DNA damage and cytotoxicity in male human peripheral blood lymphocytes. Int J Toxicol 2016; 35: 27-37
• 31 Liu X, Sen S, Liu J. et al. Antioxidant deactivation on graphenic nanocarbon surfaces. Small 2011; 7: 2775-2785
• 32 Thakkar M, Mitra S, Wei L. Effect on Growth, Photosynthesis, and oxidative stress of single walled carbon nanotubes exposure to marine alga dunaliella tertiolecta. J Nanomater 2016; 2016: pii: 8380491.