Biological Trace Element Research

, Volume 150, Issue 1–3, pp 342–349 | Cite as

Zinc Supplementation Attenuates Metallothionein and Oxidative Stress Changes in Kidney of Streptozotocin-Induced Diabetic Rats

  • Dervis Özcelik
  • Mustafa NazırogluEmail author
  • Matem Tunçdemir
  • Ömer Çelik
  • Melek Öztürk
  • M. F. Flores-Arce


Zinc is an element that under physiological conditions preferentially binds to and is a potent inducer of metallothionein under physiological conditions. The present study was conducted to explore whether zinc supplementation morphologically and biochemically protects against diabetic nephropathy through modulation of kidney metallothionein induction and oxidative stress in streptozotocin-induced diabetic rats. Thirty-two Wistar albino male rats were equally divided into four groups. The first group was used as untreated controls and the second group was supplemented with 30 mg/kg/day zinc as zinc sulfate. The third group was treated with streptozotocin to induce diabetes and the fourth group was treated with streptozotocin and supplemented with zinc as described for group 2. The blood glucose and micro-albuminuria levels, body and kidney weights were measured during the 42-day experimental period. At the end of the experiment, the kidneys were removed from all animals from the four groups. Diabetes resulted in degenerative kidney morphological changes. The metallothionein immunoreactivity level was lower and the kidney lipid peroxidation levels were higher in the diabetes group than in the controls. The metallothionein immunoreactivity levels were higher in the tubules of the zinc-supplemented diabetic rats as compared to the non-supplemented diabetic group. The zinc and metallothionein concentrations in kidney tissue were higher in the supplemented diabetic group compared to the non-supplemented diabetes group. The activity of glutathione peroxidase did not change in any of the four groups. In conclusion, the present study shows that zinc has a protective effect against diabetic damage of kidney tissue through stimulation of metallothionein synthesis and regulation of the oxidative stress.


Experimental diabetic nephropathy Oxidative stress Zinc Metallothionein Antioxidant 



The authors thank the Scientific Research Projects Coordination Unit of Istanbul University for the support of the present study (project number 3987). DÖ formulated the present hypothesis. MÖ, ÖÇ and MT were responsible for analysis of the data. MN was responsible for writing the report. MFFA made critical revision for the manuscript. Abstract of the study was published in abstract book of 4th International Congress on Cell Membranes and Oxidative Stress: Focus on Calcium Signaling and TRP Channels, 26–29 June 2012, Isparta, Turkey.

Conflict of interest

The authors declare that there are no conflicts of interest arising from their study.


  1. 1.
    Nazıroğlu M, Dikici DM, Dursun S (2012) Role of oxidative stress and Ca(2+) signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels. Neurochem Res. (ın press)Google Scholar
  2. 2.
    Özkaya D, Nazıroğlu M, Armağan A, Demirel A, Köroglu BK, Çolakoğlu N, Kükner A, Sönmez TT (2011) Dietary vitamin C and E modulates oxidative stress induced-kidney and lens injury in diabetic aged male rats through modulating glucose homeostasis and antioxidant systems. Cell Biochem Funct 29:287–293PubMedCrossRefGoogle Scholar
  3. 3.
    Salgueiro MJ, Krebs N, Zubillaga MB, Weill R, Postaire E, Lysionek AE, Caro RA, De Paoli T, Hager A, Boccio J (2001) Zinc and diabetes mellitus: is there a need of zinc supplementation in diabetes mellitus patients? Biol Trace Elem Res 81:215–228PubMedCrossRefGoogle Scholar
  4. 4.
    Batista MN, Cuppari L, de Fatima Campos Pedrosa L, Almeida MG, de Almeida JB, de Medeiros AC, Canziani ME (2006) Effect of end-stage renal disease and diabetes on zinc and copper status. Biol Trace Elem Res 112:1–12PubMedCrossRefGoogle Scholar
  5. 5.
    Özcelik D, Tuncdemir M, Özturk M, Uzun H (2011) Evaluation of trace elements and oxidative stress levels in the liver and kidney of streptozotocin-induced experimental diabetic rat model. Gen Physiol Biophys 30:356–363PubMedCrossRefGoogle Scholar
  6. 6.
    Powell SR (2000) The antioxidant properties of zinc. J Nutr 130:1447S–1454SPubMedGoogle Scholar
  7. 7.
    Brandao-Neto J, Silva CAB, Rezende AA, Almeida MG, Sales VSP, Marchini JS (2003) Zinc pharmacokinetics in insulin-dependent diabetes mellitus patients after oral zinc tolerance test. Nutr Res 23:141–150CrossRefGoogle Scholar
  8. 8.
    Adachi Y, Yoshida J, Kodera Y, Kiss T, Jakusch T, Enyedy EA, Yoshikawa Y, Sakurai H (2006) Oral administration of a zinc complex improves type diabetes and metabolic syndromes. Biochem Biophys Res Commun 351:165–170PubMedCrossRefGoogle Scholar
  9. 9.
    Alscher DM, Braun N, Biegger D, Stuelten C, Gawronski K, Murdter TE, Kuhlmann U, Fritz P (2005) Induction of metallothionein in proximal tubular cells by zinc and its potential as an endogenous antioxidant. Kidney Blood Press Res 28:127–133PubMedCrossRefGoogle Scholar
  10. 10.
    Liuzzi JP, Cousins RJ (2004) Mammalian zinc transporters. Annu Rev Nutr 24:151–172PubMedCrossRefGoogle Scholar
  11. 11.
    Zhou Z, SunX KYJ (2002) Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress. Exp Biol Med 227:214–222Google Scholar
  12. 12.
    Cai L (2004) Metallothionein as an adaptive protein prevents diabetes and its toxicity. Nonlinearity Biol-Toxicol-Med 2:89–103PubMedCrossRefGoogle Scholar
  13. 13.
    Wang J, Song Y, Elsherif L, Song Z, Zhou G, Prabhu SD, Saari JT, Cai L (2006) Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation 113:544–554PubMedCrossRefGoogle Scholar
  14. 14.
    Tunçdemir M, Ozturk M (2008) The effects of ACE inhibitor and angiotensin receptor blocker on clusterin and apoptosis in the kidney tissue of streptozotocin-diabetic rats. J Mol Histol 39:605–616PubMedCrossRefGoogle Scholar
  15. 15.
    Placer ZA, Cushman L, Johnson BC (1966) Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Anal Biochem 16:359–364PubMedCrossRefGoogle Scholar
  16. 16.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-Phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  17. 17.
    Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958PubMedCrossRefGoogle Scholar
  18. 18.
    Clegg MS, Keen CL, Lönnerdal B, Hurley LS (1981) Influence of ashing techniques in the analyses of trace elements in animal tissue. Biol Trace Elem Res 3:107–115CrossRefGoogle Scholar
  19. 19.
    Ravi K, Ramachandran B, Subramanian S (2004) Protective effect of Eugenia jambolana seed kernel on tissue antioxidants in streptozotocin induced diabetic rats. Biol Pharm Bull 27:1212–1217PubMedCrossRefGoogle Scholar
  20. 20.
    Orhan N, Berkkan A, Deliorman Orhan D, Aslan M, Ergun F (2011) Effects of Juniperus oxycedrus ssp. oxycedrus on tissue lipid peroxidation, trace elements (Cu, Zn, Fe) and blood glucose levels in experimental diabetes. J Ethnopharmacol 133:759–764PubMedCrossRefGoogle Scholar
  21. 21.
    Ziyadeh FN, Goldfarb S (1991) The renal tubulointerstitium in diabetes mellitus. Kidney Int 39:464–475PubMedCrossRefGoogle Scholar
  22. 22.
    Kelly DJ, Cox AJ, Tolcos M, Cooper ME, Wilkinson-Berka JL, Gilbert RE (2002) Attenuation of tubular apoptosis by blockade of the renin–angiotensin system in diabetic Ren-2 rats. Kidney Int 61:31–39PubMedCrossRefGoogle Scholar
  23. 23.
    Sanai T, Sobka T, Johnson T, el-Essawy M, Muchaneta-Kubara EC, Ben Gharbia O, el Oldroyd S, Nahas AM (2000) Expression of cytoskeletal proteins during the course of experimental diabetic nephropathy. Diabetologia 43:91–100PubMedCrossRefGoogle Scholar
  24. 24.
    Hill C, Flyvbjerg A, Gronbeak H, Petrik J, Hill DJ, Thomas CR, Sheppard MC, Logan A (2000) The renal expression of transforming growth factor-b isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinology 141:1196–1208PubMedCrossRefGoogle Scholar
  25. 25.
    Kovacic P, Somanathan R (2008) Unifying mechanism for eye toxicity: electron transfer, reactive oxygen species, antioxidant benefits, cell signaling and cell membranes. Cell Membr Free Radic Res 2:56–69Google Scholar
  26. 26.
    Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001PubMedCrossRefGoogle Scholar
  27. 27.
    Kakkar R, Karla J, Mantha SV, Prasad K (1995) Lipid peroxidation and activity of antioxidant enzymes in diabetic rats. Mol Cell Biochem 151:113–119PubMedCrossRefGoogle Scholar
  28. 28.
    Kutlu M, Nazıroğlu M, Simşek H, Yilmaz T, Sahap KA (2005) Moderate exercise combined with dietary vitamins C and E counteracts oxidative stress in the kidney and lens of streptozotocin-induced diabetic-rat. Int J Vitam Nutr Res 75:71–80PubMedCrossRefGoogle Scholar
  29. 29.
    Simşek M, Nazıroğlu M, Erdinç A (2005) Moderate exercise with a dietary vitamin C and E combination protects against streptozotocin-induced oxidative damage to the kidney and lens in pregnant rats. Exp Clin Endocrinol Diabetes 113:53–59PubMedCrossRefGoogle Scholar
  30. 30.
    Szczurek EI, Bjornsson CS, Noto AD, Taylor CG (2009) Renal metallothionein responds rapidly and site specifically to zinc repletion in growing rats. J Trace Elem Med Biol 23:176–182PubMedCrossRefGoogle Scholar
  31. 31.
    Li X, Cai L, Feng W (2007) Diabetes and metallothionein. Mini Rev Med Chem 7:761–768PubMedCrossRefGoogle Scholar
  32. 32.
    Dinesh Kumar S, Vijaya M, Perumal Samy R, Thameem Dheen S, Ren M, Watt F, James Kang Y, Bay BH, Tay SS (2012) Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice. Free Radic Biol Med. 10.1016/j.freeradbiomed.2012.07.008
  33. 33.
    Tang Y, Yang Q, Lu J, Zhang X, Suen D, Tan Y, Jin L, Xiao J, Xie R, Rane M, Li X, Cai L (2010) Zinc supplementation partially prevents renal pathological changes in diabetic rats. J Nutr Biochem 21:237–246PubMedCrossRefGoogle Scholar
  34. 34.
    Zou MH, Shi C, Cohen RA (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 109:817–826PubMedGoogle Scholar
  35. 35.
    Jin T, Nordberg GF, Sehlin J, Leffler P, Wu J (1994) The susceptibility of spontaneously diabetic mice to cadmium-metallothionein nephrotoxicity. Toxicology 89:81–90PubMedCrossRefGoogle Scholar
  36. 36.
    Takano H, SatohM SA, Sagai M, Yoshikawa T, Tohyama C (2000) Cytoprotection by metallothionein against gastroduodenal mucosal injury caused by ethanol in mice. Lab Invest 80:371–377PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Dervis Özcelik
    • 1
  • Mustafa Nazıroglu
    • 2
    Email author
  • Matem Tunçdemir
    • 3
  • Ömer Çelik
    • 2
  • Melek Öztürk
    • 3
  • M. F. Flores-Arce
    • 4
  1. 1.Departments of Biophysics, Cerrahpasa Medical FacultyIstanbul UniversityIstanbulTurkey
  2. 2.Department of Biophysics, Medical FacultySuleyman Demirel UniversityIspartaTurkey
  3. 3.Departments of Medical Biology, Cerrahpasa Medical FacultyIstanbul UniversityIstanbulTurkey
  4. 4.Department of Chemical and Biochemical EngineeringInstituto Tecnologico de TijuanaTijuanaMexico

Personalised recommendations