To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:1969
Key Event Title
Increase, Oxidative Stress
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of Mt-ETC complexes leading to kidney toxicity||KeyEvent||Agnes Aggy (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
“Oxidative stress is traditionally defined as an imbalance between production of ROS and endogenous antioxidants” (Small et al., 2018). Reactive Oxygen Species (ROS), the core perpetrators of oxidative stress, are highly reactive free radical oxygen molecules (Turrens, 2003; Valko et al., 2005; Hancock et al., 2001). These free radicals are strong oxidants that in high amounts, could irreversibly damage the cell and its organelles. ROS, however, are not by default detrimental to cellular function but contribute to normal activities, under physiological conditions. Reactive oxygen species can behave as signaling molecules by oxidizing proteins, lipids, and polynucleotides (Zhao et al., 2019; Hancock et al., 2001; Gorlach et al., 2015). When present in tolerable amounts, superoxides (O2-) behave as signalling molecules important in cell proliferation, hypoxia adaption, and cell fate determination but when present in excess or unregulated, induce cell damage and death (Zhao et al., 2019). Under normal oxidative phosphorylation, approximately 1-2% of the oxygen reduced by mitochondria converts into reactive oxygen species (ROS) at intermediate steps of the respiratory chain, during electron transfer (Kowaltowski and Vercesi, 1998; Volka et al., 2005; Li et al., 2003). On top of ROS generation occurring during natural cell metabolism, several other mitochondrial enzymes, such as cytochrome P450, are linked to ROS production and, interestingly many of these systems are modulated by calcium (Gorlach et al., 2015; Hancock et al., 2001). The main reasons that these antioxidant systems are in place are to regulate the constant, regular production of ROS and their signalling functionality. Oxidative stress is defined as a disruption of the pro-oxidant-antioxidant balance, favouring pro-oxidants, potentially damaging cellular components (Sies, 1991). It is important to note the fact that oxidative stress is generally caused by one of three reasons: either there is a significant increase in ROS; or there is a significant decrease in antioxidant function; or the two factors working in tandem. This distinction is crucial in determining methods of assessment of oxidative stress.
Other than mitochondrial ROS production, one of the primary producers of superoxide (O2-) is NADPH, doing so by a single electron reduction of molecular oxygen (Panday et al., 2014). NADPH oxidase, is a cytosolic-membrane protein, implicated in host defence, cellular signalling, and gene expression regulation. It is thought to produce ROS partly for defence against microbial pathogens (Panday et al., 2014). Due to its volatile nature, once formed, O2‑ released into the inter-membrane space (IMS) by CIII inevitably generates hydrogen peroxide (H2O2), a reaction is catalyzed by superoxide dismutase (SOD) (Hancock et al., 2001). Once present, the fate of H2O2 is variable and its reduction to H2O can be catalyzed by glutathione peroxidase (GPx) or peroxisomal catalase. Otherwise, it can be further converted into highly reactive hydroxyl radicals, particularly in the presence of metal ions (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010).
Under normal mitochondrial conditions, antioxidant enzymes and molecules – such as, superoxide dismutase, glutathione peroxidase, catalase, and glutathione – balance ROS generation by scavenging or binding to ROS (Santos et al., 2007). ROS disposal involves superoxide dismutase (SOD) converting O2- to H2O2, then detoxified into H2O by glutathione and catalase (Xu & Møller, 2010). Also, in case of mitochondrial damage or dysfunction, the antioxidant defence system may be impaired and its capacity drops. The resultant imbalance of the production and removal of ROS is oxidative stress. Due to the nature of oxidative stress induction and the short half-life of ROS, measuring oxidative stress through antioxidant function is a more accurate and effective way to determine the state of the cell. Oxidative stress behaves as a positive feedback loop, leading to the over-production of free-radicals as ROS further damage the mitochondria and antioxidant capacity continues to decrease (Hancock et al., 2001; Turrens, 2003; Valko et al., 2005). Antioxidant defenses can also be inhibited, further contributing to mitochondrial dysfunction; this is commonly induced by exposure to heavy metals (Blajszczak and Bonini, 2017). Due to the formation of this positive feedback loop, we experience a gap in knowledge as to which event initiated the cycle; was the increased ROS production the cause of mitochondrial dysfunction or did the mitochondrial dysfunction lead to increased ROS production?
How It Is Measured or Detected
|Assay Type & Measured Content||Description||Dose Range Studied||
Assay Characteristics (Length / Ease of use/Accuracy)
ROS Formation in the Mitochondria assay
(Shaki et al., 2012)
|“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) . In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.” (Shaki et al., 2012)||0, 50, 100 and 200 μM of Uranyl Acetate||
Mitochondrial Antioxidant Content Assay
Measuring GSH content(Shaki et al., 2012)
|“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.” (Shaki et al., 2012)||
0, 50, 100, or 200 μM Uranyl Acetate
H2O2 Production Assay
Measuring H2O2 Production in isolated mitochondria(Heyno et al., 2008)
|“Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” (Heyno et al., 2008)||
0, 10, 30 μM Cd2+2 μM antimycin A
Flow Cytometry ROS & Cell Viability(Kruiderig et al., 1997)
|“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”||
Detection of hydrogen peroxide production
(Yuan et al., 2016)
Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.
Detection of superoxide production
(Thiebault et al., 2007)
|This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.||0–600 µM||
|CM-H2DCFDA Assay||**Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)**|
Domain of Applicability
Oxidative stress can happen in all forms of life.
Evidence for Perturbation by Stressor
Kruidering et al. (1997) examined the effect of platinum on pig kidneys and found that it was able to induce significant dose-dependant ROS formation within 20 minutes of treatment administration.
In a study of the effects of aluminum treatment on rat kidneys, Al Dera (2016) found that renal GSH, SOD, and GPx levels were significantly lower in the treated groups, while lipid peroxidation levels were significantly increased.
Belyaeva et al. (2012) investigated the effect of cadmium treatment on human kidney cells. They found that cadmium was the most toxic when the sample was treated with 500 μM for 3 hours (Belyaeva et al., 2012). As this study also looked at mercury, it is worth noting that mercury was more toxic than cadmium in both 30-minute and 3-hour exposures at low concentrations (10-100 μM) (Belyaeva et al., 2012).
Wang et al. (2009) conducted a study evaluating the effects of cadmium treatment on rats and found that the treated group showed a significant increase in lipid peroxidation. They also assessed the effects of lead in this study, and found that cadmium can achieve a very similar level of lipid peroxidation at a much lower concentration than lead can, implying that cadmium is a much more toxic metal to the kidney mitochondria than lead is (Wang et al., 2009). They also found that when lead and cadmium were applied together they had an additive effect in increasing lipid peroxidation content in the renal cortex of rats (Wang et al., 2009).
Jozefczak et al. (2015) treated Arabidopsis thaliana wildtype, cad2-1 mutant, and vtc1-1 mutant plants with cadmium to determine the effects of heavy metal exposure to plant mitochondria in the roots and leaves. They found that total GSH/GSG ratios were significantly increased after cadmium exposure in the leaves of all sample varieties and that GSH content was most significantly decreased for the wildtype plant roots (Jozefczak et al., 2015).
Andjelkovic et al. (2019) also found that renal lipid peroxidation was significantly increased in rats treated with 30 mg/kg of cadmium.
Belyaeva et al. (2012) conducted a study which looked at the effects of mercury on human kidney cells, they found that mercury was the most toxic when the sample was treated with 100 μM for 30 minutes.
Buelna-Chontal et al. (2017) investigated the effects of mercury on rat kidneys and found that treated rats had higher lipid peroxidation content and reduced cytochrome c content in their kidneys.
In Shaki et al.’s article (2012), they found rat kidney mitochondria treated with uranyl acetate caused increased formation of ROS, increased lipid peroxidation, and decreased GSH content when exposed to 100 μM or more for an hour.
Hao et al. (2014), found that human kidney proximal tubular cells (HK-2 cells) treated with uranyl nitrate for 24 hours with 500 μM showed a 3.5 times increase in ROS production compared to the control. They also found that GSH content was decreased by 50% of the control when the cells were treated with uranyl nitrate (Hao et al., 2014).
Bhadauria and Flora (2007) studied the effects of arsenic treatment on rat kidneys. They found that lipid peroxidation levels were increased by 1.5 times and the GSH/GSSG ratio was decreased significantly (Bhadauria and Flora, 2007).
Kharroubi et al. (2014) also investigated the effect of arsenic treatment on rat kidneys and found that lipid peroxidation was significantly increased, while GSH content was significantly decreased.
In their study of the effects of arsenic treatment on rat kidneys, Turk et al. (2019) found that lipid peroxidation was significantly increased while GSH and GPx renal content were decreased.
Miyayama et al. (2013) investigated the effects of silver treatment on human bronchial epithelial cells and found that intracellular ROS generation was increased significantly in a dose-dependant manner when treated with 0.01 to 1.0 μM of silver nitrate.
Chtourou et al. (2012) investigated the effects of manganese treatment on rat kidneys. They found that manganese treatment caused significant increases in ROS production, lipid peroxidation, urinary H2O2 levels, and PCO production. They also found that intracellular GSH content was depleted in the treated group (Chtourou et al., 2012).
Tyagi et al. (2011) conducted a study of the effects of nickel treatment on rat kidneys. They found that the treated rats showed a significant increase in kidney lipid peroxidation and a significant decrease in GSH content in the kidney tissue (Tyagi et al., 2011).
Yeh et al. (2011) investigated the effects of zinc treatment on rat kidneys and found that treatment with 150 μM or more for 2 weeks or more caused a time- and dose-dependant increase in lipid peroxidation. They also found that renal GSH content was decreased in the rats treated with 150 μM or more for 8 weeks (Yeh et al., 2011).
It should be noted that Hao et al. (2014) found that rat kidneys exposed to lower concentrations of zinc (such as 100 μM) for short time periods (such as 1 day), showed a protective effect against toxicity induced by other heavy metals, including uranium. Soussi, Gargouri, and El Feki (2018) also found that pre-treatment with a low concentration of zinc (10 mg/kg treatment for 15 days) protected the renal cells of rats were from changes in varying oxidative stress markers, such as lipid peroxidation, protein carbonyl, and GPx levels.
Huerta-García et al. (2014) conducted a study of the effects of titanium nanoparticles on human and rat brain cells. They found that both the human and rat cells showed time-dependant increases in ROS when treated with titanium nanoparticles for 2 to 6 hours (Huerta-García et al., 2014). They also found elevated lipid peroxidation that was induced by the titanium nanoparticle treatment of human and rat cell lines in a time-dependant manner (Huerta-García et al., 2014).
Liu et al. (2010) also investigated the effects of titanium nanoparticles, however they conducted their trials on rat kidney cells. They found that ROS production was significantly increased in a dose dependant manner when treated with 10 to 100 μg/mL of titanium nanoparticles (Liu et al., 2010).
Pan et al. (2009) treated human cervix carcinoma cells with gold nanoparticles (Au1.4MS) and found that intracellular ROS content in the treated cells increased in a time-dependant manner when treated with 100 μM for 6 to 48 hours. They also compared the treatment with Au1.4MS gold nanoparticles to treatment with Au15MS treatment, which are another size of gold nanoparticle (Pan et al., 2009). The Au15MS nanoparticles were much less toxic than the Au1.4MS gold nanoparticles, even when the Au15MS nanoparticles were applied at a concentration of 1000 μM (Pan et al., 2009). When investigating further markers of oxidative stress, Pan et al. (2009) found that GSH content was greatly decreased in cells treated with gold nanoparticles.
Ferreira et al. (2015) also studied the effects of gold nanoparticles. They exposed rat kidneys to GNPs-10 (10 nm particles) and GNPs-30 (30 nm particles), and found that lipid peroxidation and protein carbonyl content in the rat kidneys treated with GNPs-30 and GNPs-10, respectively, were significantly elevated.
Adam-Vizi, V., & Starkov, A. A. (2010). Calcium and mitochondrial reactive oxygen species generation: How to read the facts. Journal of Alzheimer's Disease : JAD, 20 Suppl 2, S413-S426. doi:10.3233/JAD-2010-100465
Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J, 37(4), 369-378. doi:10.15537/smj.2016.4.13611
Andjelkovic, M., Djordjevic, A. B., Antonijevic, E., Antonijevic, B., Stanic, M., Kotur-Stevuljevic, J., . . . Bulat, Z. (2019). Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. International Journal of Environmental Research and Public Health, 16, 247. doi:10.3390/ijerph16020274
Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981
Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V., & Zakharova, I. O. (2012). Mitochondrial electron transport chain in heavy metal-induced neurotoxicity : Effects of cadmium , mercury , and copper. Thescientificworld, 2012, 1-14. doi:10.1100/2012/136063
Bhadauria, S., & Flora, S. J. S. (2007). Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats. Cell Biol Toxicol, 23, 91-104. doi:10.1007/s10565-006-0135-8
Blajszczak, C., & Bonini, M. G. (2017). Mitochondria targeting by environmental stressors : Implications for redox cellular signaling. Toxicology, 391, 84-89. doi:10.1016/j.tox.2017.07.013
Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S., Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction. Cell Biology International, 41, 1356-1366. doi:10.1002/cbin.10871
Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol, 29, 1147-1154. doi:10.1002/tox.21845
Ferreira, G. K., Cardoso, E., Vuolo, F. S., Michels, M., Zanoni, E. T., Carvalho-Silva, M., . . . Paula, M. M. S. (2015). Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats. Biochem. Cell Biol., 93, 548-557. doi:10.1139/bcb-2015-0030
Görlach, A., Bertram, K., Hudecova, S., & Krizanova, O. (2015). Calcium and ROS: A mutual interplay. Redox Biology, 6, 260-271. doi:doi:10.1016/j.redox.2015.08.010
Hancock, J. T., Desikan, R., & Neill, S. J. (2001). Role of reactive oxygen species in cell signalling pathways. Biochemical Society Transactions, 29(Pt 2), 345-350. doi:10.1042/0300-5127:0290345 [doi]
Hao, Y., Huang, J., Liu, C., Li, H., Liu, J., Zeng, Y., . . . Li, R. (2016). Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity. Scientific Reports, doi:10.1038/srep38942
Heyno, E., Klose, C., & Krieger-Liszkay, A. (2008). Origin of cadmium-induced reactive oxygen species production: Mitochondrial electron transfer versus plasma membrane NADPH oxidase. New Phytologist, 179, 687-699. doi:10.1111/j.1469-8137.2008.02512.x
Huerta-García, E., Perez-Arizti, J. A., Marquez-Ramirez, S. G., Delgado-Buenrostro, N. L., Chirino, Y. I., Iglesias, G. G., & Lopez-Marure, R. (2014). Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. Free Radical Biology and Medicine, 73, 84-94. doi:10.1016/j.freeradbiomed.2014.04.026
Jozefczak, M., Bohler, S., Schat, H., Horemans, N., Guisez, Y., Remans, T., . . . Cuypers, A. (2015). Both the concentration and redox state of glutathione and ascorbate influence the sensitivity of arabidopsis to cadmium. Annals of Botany, 116(4), 601-612. doi:10.1093/aob/mcv075
Kehrer, J. P. (2000). The Haber–Weiss reaction and mechanisms of toxicity. Toxicology, 149(1), 43-50. doi:https://doi.org/10.1016/S0300-483X(00)00231-6
Kharroubi, W., Dhibi, M., Mekni, M., Haouas, Z., Chreif, I., Neffati, F., . . . Sakly, R. (2014). Sodium arsenate induce changes in fatty acids profiles and oxidative damage in kidney of rats. Environ Sci Pollut Res, 21, 12040-12049. doi:10.1007/s11356-014-3142-y
Kowaltowski, A. J., & Vercesi, A. E. (1999). Mitochondrial damage induced by conditions of oxidative stress. Free Radical Biology and Medicine, 26(3), 463-471. doi:https://doi.org/10.1016/S0891-5849(98)00216-0
Kruidering, M., Van De Water, B., De Heer, E., Mulder, G. J., & Nagelkerke, J. F. (1997). Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. The Journal of Pharmacology and Experimental Therapeutics, 280(2), 638-649.
Li, N., Ragheb, K., Lawler, G., Sturgis, J., Melendez, J. A., & Robinson, J. P. (2003). Mitochondrial complex I inhibitor rotenone induced apoptosis through enhancing mitochondrial reactive oxygen species production. The Journal of Biological Chemistry, 278(10), 8516-8525.
Liang, Shih-Shin & Shiue, Yow-Ling & Kuo, Chao Jen & Guo, Su-Er & Liao, Wei-Ting & Tsai, Eing. (2013). Online Monitoring Oxidative Products and Metabolites of Nicotine by Free Radicals Generation with Fenton Reaction in Tandem Mass Spectrometry. TheScientificWorldJournal. 2013. 189162. 10.1155/2013/189162.
Liu, S., Xu, L., Zhang, T., Ren, G., & Yang, Z. (2010). Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. Toxicology, 267, 172-177. doi:10.1016/j.tox.2009.11.012
Lunyera, J., & Smith, S. R. (2017). Heavy metal nephropathy: Considerations for exposure analysis. Kidney International, 92, 548-550. doi:http://dx.doi.org/10.1016/j.kint.2017.04.043
Miyayama, T., Arai, Y., Suzuki, N., & Hirano, S. (2013). Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells follwoing exposure to silver nitrate. Toxicology, 305, 20-29. doi:10.1016/j.tox.2013.01.004
Pan, Y., Leifer, A., Ruau, D., Neuss, S., Bonrnemann, J., Schmid, G., . . . Jahnen-Dechent, W. (2009). Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(8), 2067-2076. doi:10.1002/smll.200900466
Panday, A., Sahoo, M., Osorio, D., Barta, S. (2014). NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 12, 5–23 (2015). https://doi.org/10.1038/cmi.2014.89
Pourahmad, J., Ghashang, M., Ettehadi, H. A., & Ghalandari, R. (2006). A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity. Environmental Toxicology, 21(4), 349-354. doi:10.1002/tox.20196
Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928
Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2
Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015
Shaki, F., Hosseini, M., Ghazi-Khansari, M., & Pourahmad, J. (2013). Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria. Metallomics, 5(6), 736-744. doi:10.1039/c3mt00019b
Sies, H. (Ed.), Oxidative Stress, Oxidants and Antioxidants, Academic Press, San Diego, CA (1991), pp. XV-XXII
Small, D. M., Sanchez, W. Y., Roy, S. F., Morais, C., Brooks, H. L., Coombes, J. S., . . . Gobe, G. (2018). N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses. American Physiological Society - Renal Physiology, 314, F956-F968. doi:10.1152/ajprenal.00057.2017
Thiébault, C., Carrière, M., Milgram, S., Simon, A., Avoscan, L., & Gouget, B. (2007). Uranium induces apoptosis and is genotoxic to normal rat kidney (NRK-52E) proximal cells. Toxicological Sciences : An Official Journal of the Society of Toxicology, 98(2), 479-487. doi:kfm130 [pii]
Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6
Turrens, J. F. (2003). Mitochondrial formation of reactive oxygen species. The Journal of Physiology, 552(Pt 2), 335-344. doi:jphysiol.2003.049478 [pii]
Tyagi, R., Rana, P., Gupta, M., Khan, A. R., Bhatnagar, D., Bhalla, P. J. S., . . . Kushu, S. (2011). Differntial biochemical response of rat kidney towards low and high doses of NiCl2 as revealed by NMR spectroscopy. Journal of Applied Toxicology, 33, 134-141. doi:10.1002/jat.1730
Valko, M., Morris, H., & Cronin, M. T. (2005). Metals, toxicity and oxidative stress. Current Medicinal Chemistry, 12(10), 1161-1208. doi:10.2174/0929867053764635 [doi]
Wang, L., Li, J., Li, J., & Liu, Z. (2009). Effects of lead and/or cadmium on the oxidative damage of rat kidney cortex mitochondria. Biol.Trace Elem.Res., 137, 69-78. doi:10.1007/s12011-009-8560-1
Xu, X. M., & Moller, G. S. (2010). ROS removal by DJ-1. Plant Signaling & Behaviour, 5(8), 1034-1036. doi:10.4161/psb.5.8.12298
Yeh, Y., Lee, Y., Hsieh, Y., & Hwang, D. (2011). Dietary taurine reduces zinc-induced toxicity in male wistar rats. Journal of Food Science, 76(4), 90-98. doi:10.1111/j.1750-3841.2011.02110.x
Yuan, Y., Zheng, J., Zhao, T., Tang, X., & Hu, N. (2016). Uranium-induced rat kidney cell cytotoxicity is mediated by decreased endogenous hydrogen sulfide (H2S) generation involved in reduced Nrf2 levels. Toxicology Research, 5(2), 660-673. doi:10.1039/C5TX00432B
Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (review). International Journal of Molecular Medicine, 44(1), 3-15. doi:10.3892/ijmm.2019.4188