Diabetes mellitus (DM) is a health problem affecting millions of individuals worldwide. Diabetic nephropathy (DN), as a significant complication of DM, has become the most common cause of endstage renal failure. Oxidative stress constitutes the key and common events in the pathogenesis of DN and antioxidants may play a beneficial role in its prevention. This study was conducted to investigate the effect of Zinc Chloride on streptozotocin-induced diabetic nephropathy in rats compared to Gliclazide, a reference antidiabetic agent. Results showed that Zinc Chloride was able to control STZ-induced DN in rats as it normalized the elevated blood pressure, the increased insulin release, and the decreased blood glucose level. Zinc Chloride also improved kidney function as determined by the restoration of blood urea and creatinine level. Finally, Zinc Chloride was able to boost the antioxidant defenses of the kidney by increasing the reduced glutathione content and decreasing lipid peroxides content in addition to significantly decreasing kidney nitric oxide content compared to diabetic control rats. These results suggest that exposure to Zinc Chloride can protect from diabetic nephropathy and can be used as an adjuvant approach to treatment and prevention of renal damage.
Shaw, J.E., Sicree, R.A. and Zimmet, P.Z. (2010) Global Estimates of the Prevalence of Diabetes for 2010 and 2030. Diabetes Research and Clinical Practice, 87, 4-14. http://dx.doi.org/10.1016/j.diabres.2009.10.007
Wild, S., et al. (2004) Global Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030. Diabetes Care, 27, 1047-1053. http://dx.doi.org/10.2337/diacare.27.5.1047
Elmarakby, A.A. and Sullivan, J.C. (2012) Relationship between Oxidative Stress and Inflammatory Cytokines in Diabetic Nephropathy. Cardiovascular Therapeutics, 30, 49-59. http://dx.doi.org/10.1111/j.1755-5922.2010.00218.x
Shi, Y. and Vanhoutte, P.M. (2009) Reactive Oxygen-Derived Free Radicals Are Key to the Endothelial Dysfunction of Diabetes. Journal of Diabetes, 1, 151-162. http://dx.doi.org/10.1111/j.1753-0407.2009.00030.x
Tiganis, T. (2011) Reactive Oxygen Species and Insulin Resistance: The Good, the Bad and the Ugly. Trends in Pharmacological Sciences, 32, 82-89. http://dx.doi.org/10.1016/j.tips.2010.11.006
Pitocco, D., et al. (2010) Oxidative Stress, Nitric Oxide, and Diabetes. The Review of Diabetic Studies, 7, 15-25. http://dx.doi.org/10.1900/RDS.2010.7.15
Rotruck, J.T., et al. (1973) Selenium: Biochemical Role as a Component of Glutathione Peroxidase. Science, 179, 588-590. http://dx.doi.org/10.1126/science.179.4073.588
Beem, K.M., Richardson, D.C. and Rajagopalan, K.V. (1977) Metal Sites of Copper-Zinc Superoxide Dismutase. Biochemistry, 16, 1930-1936. http://dx.doi.org/10.1021/bi00628a027
Horn Jr., A., et al. (2010) An Iron-Based Cytosolic Catalase and Superoxide Dismutase Mimic Complex. Inorganic Chemistry, 49, 1274-1276. http://dx.doi.org/10.1021/ic901904b
Aly, H.F. and Mantawy, M.M. (2012) Comparative Effects of Zinc, Selenium and Vitamin E or Their Combination on Carbohydrate Metabolizing Enzymes and Oxidative Stress in Streptozotocin Induced-Diabetic Rats. European Review for Medical and Pharmacological Sciences, 16, 66-78.
Bonnefont-Rousselot, D., et al. [Diabetes Mellitus, Oxidative Stress and Advanced Glycation Endproducts]. Annales Pharmaceutiques Françaises, 62, 147-157. http://dx.doi.org/10.1016/S0003-4509(04)94297-6
Brownlee, M. (2001) Biochemistry and Molecular Cell Biology of Diabetic Complications. Nature, 414, 813-820. http://dx.doi.org/10.1038/414813a
Susztak, K., et al. (2006) Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podocyte Depletion at the Onset of Diabetic Nephropathy. Diabetes, 55, 225-233. http://dx.doi.org/10.2337/diabetes.55.01.06.db05-0894
Horie, K., et al. (1997) Immunohistochemical Colocalization of Glycoxidation Products and Lipid Peroxidation Products in Diabetic Renal Glomerular Lesions. Implication for Glycoxidative Stress in the Pathogenesis of Diabetic Nephropathy. Journal of Clinical Investigation, 100, 2995-3004. http://dx.doi.org/10.1172/JCI119853
Dobashi, K., et al. (1991) Effect of Diabetes Mellitus Induced by Streptozotocin on Renal Superoxide Dismutases in the Rat. A Radioimmunoassay and Immunohistochemical Study. Virchows Archiv. B, Cell Pathology including Molecular Pathology, 60, 67-72. http://dx.doi.org/10.1007/BF02899529
Schnackenberg, C.G. and Wilcox, C.S. (2001) The SOD Mimetic Tempol Restores Vasodilation in Afferent Arterioles of Experimental Diabetes. Kidney International, 59, 1859-1864. http://dx.doi.org/10.1046/j.1523-1755.2001.0590051859.x
Melhem, M.F., et al. (2002) Alpha-Lipoic Acid Attenuates Hyperglycemia and Prevents Glomerular Mesangial Matrix Expansion in Diabetes. Journal of the American Society of Nephrology, 13, 108-116.
Melhem, M.F., Craven, P.A. and Derubertis, F.R. (2001) Effects of Dietary Supplementation of Alpha-Lipoic Acid on Early Glomerular Injury in Diabetes Mellitus. Journal of the American Society of Nephrology, 12, 124-133.
Fioretto, P., et al. (1998) Reversal of Lesions of Diabetic Nephropathy after Pancreas Transplantation. The New England Journal of Medicine, 339, 69-75. http://dx.doi.org/10.1056/NEJM199807093390202
Palsamy, P. and Subramanian, S. (2011) Resveratrol Protects Diabetic Kidney by Attenuating Hyperglycemia-Mediated Oxidative Stress and Renal Inflammatory Cytokines via Nrf2-Keap1 Signaling. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1812, 719-731. http://dx.doi.org/10.1016/j.bbadis.2011.03.008
Jansen, J., Karges, W. and Rink, L. (2009) Zinc and Diabetes—Clinical Links and Molecular Mechanisms. The Journal of Nutritional Biochemistry, 20, 399-417. http://dx.doi.org/10.1016/j.jnutbio.2009.01.009
Cortese, M.M., Suschek, C.V., Wetzel, W., KrÖncke, K.-D. and Kolb-Bachofen, V. (2008) Zinc Protects Endothelial Cells from Hydrogen Peroxide via Nrf2-Dependent Stimulation of Glutathione Biosynthesis. Free Radical Biology and Medicine, 44, 2002-2012. http://dx.doi.org/10.1016/j.freeradbiomed.2008.02.013
Yoon, J.S. (2008) Zinc Status and Dietary Quality of Type 2 Diabetic Patients: Implication of Physical Activity Level. Nutrition Research and Practice, 2, 41-45. http://dx.doi.org/10.4162/nrp.2008.2.1.41
Kazi, T.G., et al. (2008) Copper, Chromium, Manganese, Iron, Nickel, and Zinc Levels in Biological Samples of Diabetes Mellitus Patients. Biological Trace Element Research, 122, 1-18. http://dx.doi.org/10.1007/s12011-007-8062-y
Basaki, M., Saeb, M., Nazifi, S. and Shamsaei, H.A. (2012) Zinc, Copper, Iron, and Chromium Concentrations in Young Patients with Type 2 Diabetes Mellitus. Biological Trace Element Research, 148, 161-164. http://dx.doi.org/10.1007/s12011-012-9360-6
Jansen, J., et al. (2012) Disturbed Zinc Homeostasis in Diabetic Patients by in Vitro and in Vivo Analysis of Insulinomimetic Activity of Zinc. The Journal of Nutritional Biochemistry, 23, 1458-1466. http://dx.doi.org/10.1016/j.jnutbio.2011.09.008
Asri-Rezaei, S., Tamaddonfard, E., Ghasemsoltani-Momtaz, B., Erfanparast, A. and Gholamalipour, S. (2015) Effects of Crocin and Zinc Chloride on Blood Levels of Zinc and Metabolic and Oxidative Parameters in Streptozotocin-Induced Diabetic Rats. Avicenna Journal of Phytomedicine, 5, 403-412.
Sassy-Prigent, C., et al. (1995) Morphometric Detection of Incipient Glomerular Lesions in Diabetic Nephropathy in Rats. Protective Effects of ACE Inhibition. Laboratory Investigation, 73, 64-71.
Tanwar, R.S., Sharma, S.B., Singh, U.R. and Prabhu, K.M. (2010) Attenuation of Renal Dysfunction by Anti-Hyperglycemic Compound Isolated from Fruit Pulp of Eugenia jambolana in Streptozotocin-Induced Diabetic Rats. Indian Journal of Biochemistry & Biophysics, 47, 83-89.
Hosokawa, M., Dolci, W. and Thorens, B. (2001) Differential Sensitivity of GLUT1-and GLUT2-Expressing Beta Cells to Streptozotocin. Biochemical and Biophysical Research Communications, 289, 1114-1117. http://dx.doi.org/10.1006/bbrc.2001.6145
Friederich, M., Hansell, P. and Palm, F. (2009) Diabetes, Oxidative Stress, Nitric Oxide and Mitochondria Function. Current Diabetes Reviews, 5, 120-144. http://dx.doi.org/10.2174/157339909788166800
Raza, H., Prabu, S.K., John, A. and Avadhani, N.G. (2011) Impaired Mitochondrial Respiratory Functions and Oxidative Stress in Streptozotocin-Induced Diabetic Rats. International Journal of Molecular Sciences, 12, 3133-3147. http://dx.doi.org/10.3390/ijms12053133
Ezel, T., et al. (2015) Biochemical and Histopathological Investigation of Resveratrol, Gliclazide, and Losartan Protective Effects on Renal Damage in a Diabetic Rat Model. Analytical and Quantitative Cytology and Histology, 37, 187- 198.
Kumarappan, C.T. and Mandal, S.C. (2008) Polyphenolic Extract of Ichnocarpus frutescens Attenuates Diabetic Complications in Streptozotocin-Treated Diabetic Rats. Renal Failure, 30, 307-322. http://dx.doi.org/10.1080/08860220701857449
Attia, H.N., et al. (2012) Protective Effects of Combined Therapy of Gliclazide with Curcumin in Experimental Diabetic Neuropathy in Rats. Behavioural Pharmacology, 23, 153-161. http://dx.doi.org/10.1097/FBP.0b013e3283512c00
Ohkawa, H., Ohishi, N. and Yagi, K. (1979) Assay for Lipid Peroxides in Animal Tissues by Thiobarbituric Acid Reaction. Analytical Biochemistry, 95, 351-358. http://dx.doi.org/10.1016/0003-2697(79)90738-3
Ellman, G.L. (1959) Tissue Sulfhydryl Groups. Archives of Biochemistry and Biophysics, 82, 70-77. http://dx.doi.org/10.1016/0003-9861(59)90090-6
Park, S.W., et al. (2008) Artemisia asiatica Extracts Protect against Ethanol-Induced Injury in Gastric Mucosa of Rats. Journal of Gastroenterology and Hepatology, 23, 976-984. http://dx.doi.org/10.1111/j.1440-1746.2008.05333.x
Laing, S.P., et al. (2003) Mortality from Heart Disease in a Cohort of 23,000 Patients with Insulin-Treated Diabetes. Diabetologia, 46, 760-765. http://dx.doi.org/10.1007/s00125-003-1116-6
Agarwal, S.K. and Dash, S.C. (2000) Spectrum of Renal Diseases in Indian Adults. The Journal of the Association of Physicians of India, 48, 594-600.
Cefalu, W.T. and Ratner, R.E. (2014) The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: The “Gift” That Keeps on Giving! Diabetes Care, 37, 5-7. http://dx.doi.org/10.2337/dc13-2369
Han, X., Patters, A.B., Ito, T., Azuma, J., Schaffer, S.W. and Chesney, R.W. (2015) Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy. PLoS ONE, 10, e0117718. http://dx.doi.org/10.1371/journal.pone.0117718
Li, B., et al. (2014) Zinc Is Essential for the Transcription Function of Nrf2 in Human Renal Tubule Cells in Vitro and Mouse Kidney in Vivo under the Diabetic Condition. Journal of Cellular and Molecular Medicine, 18, 895-906. http://dx.doi.org/10.1111/jcmm.12239
Dhein, S., et al. (2000) Long-Term Effects of the Endothelin(A) Receptor Antagonist LU 135252 and the Angiotensin-Converting Enzyme Inhibitor Trandolapril on Diabetic Angiopathy and Nephropathy in a Chronic Type I Diabetes Mellitus Rat Model. Journal of Pharmacology and Experimental Therapeutics, 293, 351-359.
Moreau, R., et al. (1994) Effects of Glibenclamide on Systemic and Splanchnic Haemodynamics in Conscious Rats. British Journal of Pharmacology, 112, 649-653. http://dx.doi.org/10.1111/j.1476-5381.1994.tb13124.x
Williams, S., et al. (1998) Effects of Glibenclamide on Blood Pressure and Cardiovascular Responsiveness in Non-Insulin Dependent Diabetes Mellitus. Journal of Hypertension, 16, 705-711. http://dx.doi.org/10.1097/00004872-199816050-00019
Kulkarni, J.S., Metha, A.A., Santani, D.D. and Goyal, R.K. (2002) Effects of Chronic Treatment with Cromakalim and Glibenclamide in Alloxan-Induced Diabetic Rats. Pharmacological Research, 46, 101-105. http://dx.doi.org/10.1016/S1043-6618(02)00078-6
Cohen, M.P., Clements, R.S., Cohen, J.A. and Shearman, C.W. (1996) Prevention of Decline in Renal Function in the Diabetic db/db Mouse. Diabetologia, 39, 270-274. http://dx.doi.org/10.1007/BF00418341
Montilla, P., et al. (2005) Red Wine Prevents Brain Oxidative Stress and Nephropathy in Streptozotocin-Induced Diabetic Rats. Journal of Biochemistry and Molecular Biology, 38, 539-544. http://dx.doi.org/10.5483/BMBRep.2005.38.5.539
Clark, T.A., et al. (2004) Codelivery of a Tea Extract Prevents Morbidity and Mortality Associated with Oral Vanadate Therapy in Streptozotocin-Induced Diabetic Rats. Metabolism, 53, 1145-1151. http://dx.doi.org/10.1016/j.metabol.2004.03.017