Manganese-Induced Nephrotoxicity Is Mediated through Oxidative Stress and Mitochondrial Impairment

Main Article Content

Amir Mohammad Niknahad
Mohammad Mehdi Ommati
Omid Farshad
Leila Moezi
Reza Heidari


energy crisis, manganism, mitochondria, renal failure, serum electrolyte waste


Manganese (Mn) is an essential element that is incorporated in various metabolic pathways and enzyme structures. On the other hand, a range of adverse effects has been described in association with Mn overexposure. Mn is a well-known neurotoxic agent in mammals. Renal injury is another adverse effect associated with Mn intoxication. No precise mechanism for Mn nephrotoxicity has been identified so far. The current study was designed to evaluate the potential mechanisms of Mn-induced renal injury. Rats were treated with Mn (20 and 40 mg/mL, respectively, in drinking water) for 30 consecutive days. Markers of oxidative stress, as well as several mitochondrial indices, were assessed in the kidney tissue. Renal injury was evident in Mn-treated animals, as judged by a significant increase in serum BUN and creatinine. Moreover, urinalysis revealed a significant increase in urine glucose, phosphate, and protein in Mn-treated rats. Kidney histopathological alterations, including tubular atrophy, interstitial inflammation, and necrosis, were also detected in Mn-treated animals. Biomarkers of oxidative stress, including an increment in reactive oxygen species (ROS), lipid peroxidation, and oxidized glutathione (GSSG), were detected in Mn-treated groups. On the other hand, kidney glutathione (GSH) stores and total antioxidant capacity were depleted in Mn groups. Mn exposure was associated with significant mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depletion of adenosine tri-phosphate (ATP) content. These data highlight oxidative stress and mitochondrial impairment as potential mechanisms involved in Mn-induced renal injury.


Download data is not yet available.
Abstract 341 | PDF Downloads 14 HTML Downloads 5 XML Downloads 25


1. Santamaria AB. Manganese exposure, essentiality & toxicity. Indian J Med Res. 2008;128(4):484–500.
2. Costa LG, Aschner M. Manganese in health and disease. London: Royal Society of Chemistry; 2014. 655 p.
3. Aschner M, Aschner JL. Manganese neurotoxicity: Cellular effects and blood-brain barrier transport. Neurosci Biobehav Rev. 1991;15(3):333–40. S0149-7634(05)80026-0
4. Dobson AW, Erikson KM, Aschner M. Manganese neurotox-icity. Ann N Y Acad Sci. 2004;1012(1):115–28. http://dx.doi. org/10.1196/annals.1306.009
5. Pal PK, Samii A, Calne DB. Manganese neurotoxicity: A review of clinical features, imaging and pathology. Neurotoxicology. 1998;20(2–3):227–38.
6. Huang W-H, Lin J-L. Acute renal failure following ingestion of manganese-containing fertilizer. Clin Toxicol. 2004;42(3):305–7.
7. Chtourou Y, Garoui EM, Boudawara T, Zeghal N. Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol. 2014;29(10):1147–54.
8. Sánchez-González C, López-Chaves C, Gómez-Aracena  J, Galindo P, Aranda P, Llopis J. Association of plasma manganese levels with chronic renal failure. J Trace Elem Med Biol. 2015;31:78–84.
9. Racette BA, Aschner M, Guilarte TR, Dydak U, Criswell SR, Zheng W. Pathophysiology of manganese-associated neuro-toxicity. Neurotoxicology. 2012;33(4):881–6. http://dx.doi. org/10.1016/j.neuro.2011.12.010
10. Eftekhari A, Ahmadian E, Azarmi Y, Parvizpur A, Fard JK, Eghbal MA. The effects of cimetidine, N-acetylcysteine, and taurine on thioridazine metabolic activation and induction of oxidative stress in isolated rat hepatocytes. Pharm Chem J. 2018;51(11):965–9.
11. Ommati MM, Heidari R, Ghanbarinejad V, Abdoli N, Niknahad  H. Taurine treatment provides neuroprotec-tion in a mouse model of manganism. Biol Trace Elem Res. 2018;190(2):384–95.
12. Heidari R, Behnamrad S, Khodami Z, Ommati MM, Azarpira  N, Vazin A. The nephroprotective properties of tau-rine in colistin-treated mice is mediated through the regula-tion of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother. 2019;109:103–11. http://dx.doi. org/10.1016/j.biopha.2018.10.093
13. Verity MA. Manganese neurotoxicity: A mechanistic hypothe-sis. Neurotoxicology. 1999;20(2–3):489–97.
14. Chakraborti S, Rahaman SM, Alam MN, Mandal A, Ghosh B, Dey K, Chakraborti T. Na+/K+-ATPase: A perspective. In: Chakraborti S, Dhalla NS, editors. Regulation of membrane Na+-K+ ATPase. Advances in biochemistry in health and dis-ease. New York: Springer International Publishing; 2016. p. 3–30.
15. Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol. 2017;13(10):629–46. http://dx.doi. org/10.1038/nrneph.2017.107
16. Heidari R. The footprints of mitochondrial impairment and cellular energy crisis in the pathogenesis of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and Fanconi’s syndrome: A comprehensive review. Toxicology. 2019;423:1–31.
17. Ralto KM, Parikh SM, editors. Mitochondria in acute kid-ney injury. Semin Nephrol. 2016;36(1):8–16. http://dx.doi. org/10.1016/j.semnephrol.2016.01.005
18. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol. 2004;287(4):C817–33. ajpcell.00139.2004
19. Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N, et al. Dithiothreitol supplementa-tion mitigates hepatic and renal injury in bile duct ligated mice: Potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother. 2018;99:1022–32. http://
20. Ommati MM, Heidari R, Zamiri MJ, Sabouri S, Zaker L, Farshad O, et al. The footprints of oxidative stress and mito-chondrial impairment in arsenic trioxide-induced testosterone release suppression in pubertal and mature F1-male Balb/c mice via the downregulation of 3β-HSD, 17β-HSD, and CYP11a expression. Biol Trace Elem Res. 2020;95(1):125–34. http://dx.
21. Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, et al. Mitochondria protection as a mech-anism underlying the hepatoprotective effects of glycine in choles-tatic mice. Biomed Pharmacother. 2018;97(Supplement C):1086–95.
22. Jamshidzadeh A, Heidari R, Latifpour Z, Ommati MM, Abdoli N, Mousavi S, et al. Carnosine ameliorates liver fibro-sis and hyperammonemia in cirrhotic rats. Clin Res Hepatol Gastroenterol. 2017;41(4):424–34. clinre.2016.12.010
23. Truong DH, Eghbal MA, Hindmarsh W, Roth SH, O’Brien  PJ. Molecular mechanisms of hydrogen sulfide tox-icity. Drug Metab Rev. 2006;38(4):733–44. http://dx.doi. org/10.1080/03602530600959607
24. Heidari R, Mandegani L, Ghanbarinejad V, Siavashpour A, Ommati MM, Azarpira N, et al. Mitochondrial dysfunction as a mechanism involved in the pathogenesis of cirrhosis-associated cholemic nephropathy. Biomed Pharmacother. 2019;109:271–80.
25. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz  A-G, et al. Determination of carbonyl content in oxida-tively modified proteins. Methods Enzymol. 1990;186:464–78.
26. Jamshidzadeh A, Heidari R, Mohammadi-Samani S, Azarpira N, Najbi A, Jahani P, et al. A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice. J Biochem Mol Toxicol. 2015;29(2):57–62. http://dx.doi. org/10.1002/jbt.21667
27. Ommati M, Heidari R, Manthari R, Tikka SCJ, Niu R, Sun Z, et al. Paternal exposure to arsenic resulted in oxidative stress, autophagy, and mitochondrial impairments in the HPG axis of pubertal male offspring. Chemosphere. 2019;236:124325. http://
28. Kihira T, Mukoyama M, Ando K, Yase Y, Yasui M. Determination of manganese concentrations in the spinal cords from amyotrophic lateral sclerosis patients by inductively cou-pled plasma emission spectroscopy. J Neurol Sci. 1990;98(2):251– 8.
29. Fernández-Vizarra E, Ferrín G, Pérez-Martos A, Fernández-Silva P, Zeviani M, Enríquez JA. Isolation of mitochon-dria for biogenetical studies: An update. Mitochondrion. 2010;10(3):253–62.
30. Ommati MM, Jamshidzadeh A, Heidari R, Sun Z, Zamiri MJ, Khodaei F, et al. Carnosine and histidine supplementation blunt lead-induced reproductive toxicity through antioxidative and mitochondria-dependent mechanisms. Biol Trace Elem Res. 2018;187:151–62.
31. Chen Y, Xing D, Wang W, Ding Y, Du L. Development of an ion-pair HPLC method for investigation of energy charge changes in cerebral ischemia of mice and hypoxia of Neuro-2a cell line. Biomed Chromatogr. 2007;21(6):628–34. http://dx.doi. org/10.1002/bmc.798
32. Heidari R, Jafari F, Khodaei F, Shirazi Yeganeh B, Niknahad H. Mechanism of valproic acid-induced Fanconi syndrome involves mitochondrial dysfunction and oxidative stress in rat kidney. Nephrology. 2018;23(4):351–61.
33. Ahmadian E, Babaei H, Mohajjel Nayebi A, Eftekhari A, Eghbal MA. Mechanistic approach for toxic effects of bupro-pion in primary rat hepatocytes. Drug Res. 2017;67(4):217–22.
34. Heidari R, Niknahad H. The role and study of mitochondrial impairment and oxidative stress in cholestasis. In: Vinken M, editor. Experimental cholestasis research. Methods in molecular biology. New York, NY: Springer; 2019. p. 117–32.
35. Ommati MM, Heidari R, Jamshidzadeh A, Zamiri MJ, Sun Z, Sabouri S, et al. Dual effects of sulfasalazine on rat sperm characteristics, spermatogenesis, and steroidogenesis in two experimental models. Toxicol Lett. 2018;284:46–55. http://dx.
36. Heidari R, Niknahad H, Sadeghi A, Mohammadi H, Ghanbarinejad V, Ommati MM, et al. Betaine treatment pro-tects liver through regulating mitochondrial function and coun-teracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother. 2018;103:75–86. http://
37. Caro AA, Adlong LW, Crocker SJ, Gardner MW, Luikart EF, Gron LU. Effect of garlic-derived organosulfur compounds on mitochondrial function and integrity in isolated mouse liver mitochondria. Toxicol Lett. 2012;214(2):166–74. http://dx.doi. org/10.1016/j.toxlet.2012.08.017
38. Sánchez B, Casalots-Casado J, Quintana S, Arroyo A, Martín-Fumadó C, Galtés I. Fatal manganese intoxication due to an error in the elaboration of Epsom salts for a liver cleansing diet. Forensic Sci Int. 2012;223(1–3):e1–4. forsciint.2012.07.010
39. Young RJ, Critchley JA, Young KK, Freebairn RC, Reynolds AP, Lolin YI. Fatal acute hepatorenal failure following potassium permanganate ingestion. Hum Exp Toxicol. 1996;15(3):259–61.
40. Agrawal VK, Bansal A, Kumar R, Kumawat BL, Mahajan P. Potassium permanganate toxicity: A rare case with difficult airway management and hepatic damage. Indian J Crit Care Med. 2014;18(12):819–21.
41. Taylor PA, Price JD. Acute manganese intoxication and pan-creatitis in a patient treated with a contaminated dialysate. Can Med Assoc J. 1982;126(5):503–5.
42. Erikson KM, Aschner M. Manganese neurotoxicity and gluta-mate-GABA interaction. Neurochem Int. 2003;43(4–5):475–80.
43. Erikson KM, Dobson AW, Dorman DC, Aschner M. Manganese exposure and induced oxidative stress in the rat brain. Sci Total Environ. 2004;334–335:409–16. http://dx.doi. org/10.1016/j.scitotenv.2004.04.044
44. Zwingmann C, Leibfritz D, Hazell AS. Brain energy metabo-lism in a sub-acute rat model of manganese neurotoxicity: An ex vivo nuclear magnetic resonance study using [1-13C]glucose. Neurotoxicology. 2004;25(4):573–87. neuro.2003.08.002
45. Sarkar S, Malovic E, Harischandra DS, Ngwa HA, Ghosh A, Hogan C, et al. Manganese exposure induces neuroinflam-mation by impairing mitochondrial dynamics in astrocytes. Neurotoxicology. 2018;64:204–18. neuro.2017.05.009