Abstract
Diabetic nephropathy is both a common and a severe complication of diabetes mellitus. Iron is an essential trace element. However, excess iron is toxic, playing a role in the pathogenesis of diabetic nephropathy. The present study aimed to determine the extent of the interaction between iron and type 2 diabetes in the kidney. Male rats were randomly assigned into four groups: control, iron (300-mg/kg iron dextran), diabetes (a single dose of intraperitoneal streptozotocin), and iron + diabetes group. Iron supplementation resulted in a higher liver iron content, and diabetic rats showed higher serum glucose compared with control rats, which confirmed the model as iron overload and diabetic. It was found that iron + diabetes group showed a greater degree of kidney pathological changes, a remarkable reduction in body weight, and a significant increase in relative kidney weight and iron accumulation in rat kidneys compared with iron or diabetes group. Moreover, malondialdehyde values in the kidney were higher in iron + diabetes group than in iron or diabetes group, sulfhydryl concentration and glutathione peroxidase activity were decreased by the diabetes and iron + diabetes groups, and protein oxidation and nitration levels were higher in the kidney of iron + diabetes group as compared to iron or diabetes group. However, iron supplementation did not elevate the glucose level of a diabetic further. These results suggested that iron increased the diabetic renal injury probably through increased oxidative/nitrative stress and reduced antioxidant capacity instead of promoting a rise in blood sugar levels; iron might be a potential cofactor of diabetic nephropathy, and strict control of iron would be important under diabetic state.
Similar content being viewed by others
References
Forbes JM, Coughlan MT, Cooper ME (2008) Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 57(6):1446–1454
Özkaya D, Naziroğlu M, Armağan A et al (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(4):287–293
Özcelik D, Nazıroglu M, Tunçdemir M et al (2012) Zinc supplementation attenuates metallothionein and oxidative stress changes in kidney of streptozotocin-induced diabetic rats. Biol Trace Elem Res 150:342–349
Naziroğlu M (2003) Enhanced testicular antioxidant capacity in streptozotocin-induced diabetic rats: protective role of vitamins C and E and selenium. Biol Trace Elem Res 94(1):61–72
Larkins RG, Dunlop ME (1992) The link between hyperglycaemia and diabetic nephropathy. Diabetologia 35(6):499–504
Halliwell B, Gutteridge J (1984) Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 219(1):1–14
Awai M, Narasaki M, Yamanoi Y, Seno S (1979) Induction of diabetes in animals by parenteral administration of ferric nitrilotriacetate. A model of experimental hemochromatosis. Am J Pathol 95(3):663–673
Tuomainen TP, Nyyssönen K, Salonen R et al (1997) Body iron stores are associated with serum insulin and blood glucose concentrations: population study in 1,013 eastern Finnish men. Diabetes Care 20(3):426–428
Rajpathak SN, Crandall JP, Wylie-Rosett J et al (2009) The role of iron in type 2 diabetes in humans. BBA Gen Subj 1790(7):671–681
Jiang R, Manson JE, Meigs JB et al (2004) Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. Jama J Am Med Assoc 291(6):711–717
Bao W, Rong Y, Rong S, Liu L (2012) Dietary iron intake, body iron stores, and the risk of type 2 diabetes: a systematic review and meta-analysis. BMC Med 10(1):119
Ford ES, Cogswell ME (1999) Diabetes and serum ferritin concentration among US adults. Diabetes Care 22(12):1978–1983
Eshed I, Elis A, Lishner M (2001) Plasma ferritin and type 2 diabetes mellitus: a critical review. Endocr Res 27(1–2):91–97
Arredondo M, Fuentes M, Jorquera D et al (2011) Cross-talk between body iron stores and diabetes: iron stores are associated with activity and microsatellite polymorphism of the heme oxygenase and type 2 diabetes. Biol Trace Elem Res 143(2):625–636
Fernández-Real JM, Penãrroja G, Castro A et al (2002) Blood letting in high ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 51:1000–1004
Ascherio A, Rimm EB, Giovannucci E et al (2001) Blood donations and risk of coronary heart disease in men. Circulation 103(1):52–57
Cooksey RC, Jones D, Gabrielsen S et al (2010) Dietary iron restriction or iron chelation protects from diabetes and loss of β-cell function in the obese (ob/ob lep-/-) mouse. Am J Physiol Endocrinol Metab 298(6):E1236–E1243
Minamiyama Y, Takemura S, Kodai S et al (2010) Iron restriction improves type 2 diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats. Am J Physiol Endocrinol Metab 298(6):E1140–E1149
Wolff SP (1993) Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 49(3):642–652
Swaminathan S, Fonseca VA, Alam MG, Shah SV (2007) The role of iron in diabetes and its complications. Diabetes Care 30(7):1926–1933
Li X, Li H, Lu N et al (2012) Iron increases liver injury through oxidative/nitrative stress in diabetic rats: involvement of nitrotyrosination of glucokinase. Biochimie 94(12):2620–2627
Fung TT, Schulze M, Manson JE et al (2004) Dietary patterns, meat intake, and the risk of type 2 diabetes in women. Arch Intern Med 164(20):2235–2240
Li H, Li SJ, Zhao Z et al (2008) Body iron stores and dietary iron intake in relation to diabetes in adults in North China. Diabetes Care 31(2):285–286
Zhang Y, Huang Y, Deng X et al (2012) Iron overload-induced rat liver injury: involvement of protein tyrosine nitration and the effect of baicalin. Eur J Pharmacol 680(1):95–101
Olynyk JK, O'Neill R, Britton RS, Bacon BR (1994) Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: diagnostic implications. Gastroenterology 106:674–677
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1):248–254
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and non-protein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25:192–205
Piperno A (1998) Classification and diagnosis of iron overload. Haematologica 83(5):447–455
Fischer JG, Glauert HP, Yin T et al (2002) Moderate iron overload enhances lipid peroxidation in livers of rats, but does not affect NF-κB activation induced by the peroxisome proliferator, Wy-14,643. J Nutr 132(9):2525–2531
Luan J, Li W, Han J et al (2012) Renal Protection of in vivo administration of Tempol in streptozotocin-induced Diabetic Rats. J Pharmacol Sci 119(2):167–176
Kutlu M, Naziroğlu M, Simşek H et al (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 75:71–80
Simşek M, Naziroğlu 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 113:53–59
Orhan N, Berkkan A, Deliorman Orhan D et al (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(2):759–764
Saravanan G, Ponmurugan P (2011) Ameliorative potential of S-allyl cysteine on oxidative stress in STZ induced diabetic rats. Chem Biol Interact 189(1):100–106
Mieyal JJ, Chock PB (2012) Posttranslational modification of cysteine in redox signaling and oxidative stress: focus on S-glutathionylation. Antioxid Redox Signal 16(6):471–475
Lu N, Zhang Y, Li H et al (2010) Oxidative and nitrative modifications of α-enolase in cardiac proteins from diabetic rats. Free Radic Biol Med 48(7):873–881
Ishii N, Carmines PK, Yokoba M et al (2013) Angiotensin-converting enzyme inhibition curbs tyrosine nitration of mitochondrial proteins in the renal cortex during the early stage of diabetes mellitus in rats. Clin Sci 124(8):543–552
Papanikolaou G, Pantopoulos K (2005) Iron metabolism and toxicity. Toxicol Appl Pharmacol 202(2):199–211
West IC (2000) Radicals and oxidative stress in diabetes. Diabet Med 17(3):171–180
Oteiza PI, Kleinman CG, Demasi M, Bechara EJ (1995) 5-Aminolevulinic acid induces iron release from ferritin. Arch Biochem Biophys 316(1):607–611
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (grant number 30670481), the Fundamental Research Funds for the Central Universities (HUST No. 2013QN156).
Conflict of Interest
The authors declare that no conflicts of interest exist.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gao, W., Li, X., Gao, Z. et al. Iron Increases Diabetes-Induced Kidney Injury and Oxidative Stress in Rats. Biol Trace Elem Res 160, 368–375 (2014). https://doi.org/10.1007/s12011-014-0021-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-014-0021-9