Effect of Carnosine on Renal Function, Oxidation and Glycation Products in the Kidneys of High-Fat Diet/Streptozotocin-Induced Diabetic Rats

Abstract

Background

High fat diet (HFD) and low dose of streptozotocin (STZ)-treated rats provide an animal model for type 2 Diabetes Mellitus (T2DM). Oxidative stress plays a role in the development of diabetic complications. Carnosine (CAR) has antioxidant and antiglycating properties. We investigated effects of CAR on renal function, oxidation and glycation products in HFD+STZ-rats.

Materials and Methods

Rats were fed with HFD (60% of total calories from fat) for 4 weeks and then a single dose STZ (40 mg/kg; i.p.) was applied. Rats with blood glucose levels above 200 mg/dL were fed with HFD until the end of the 12^th week. CAR (250 mg/kg body weight; i.p.; 5 times a week) was administered to rats for the last 4 weeks. Glycated hemoglobin (HbA1c), glucose, lipids, and andrenal function tests in serum as well as reactive oxygen species, malondialdehyde, protein carbonyl, advanced oxidation protein products, advanced glycation end products (AGEs), antioxidant power, and antioxidant enzyme activities and their mRNA expressions in kidneys were determined.

Results

CAR treatment did not alter glucose and HbA1c, but it decreased serum lipids, creatinine, and urea levels in HFD+STZ rats. Oxidation products of lipids and proteins and AGEs levels decreased, but antioxidant enzyme activities and their mRNA expressions remained unchanged due to CAR treatment.

Conclusion

Our results indicate that CAR treatment alleviated renal function and decreased accumulation of oxidation and glycation products in kidneys in HFD+STZ-rats.

Key words

carnosine - high fat diet - streptozotocin - oxidative stress - advanced glycation end products - renal function

• References

• 1 Kawahito S, Kitahata H, Oshita S. Problems associated with glucose toxicity: Role of hyperglycemia-induced oxidative stress. World J Gastroenterol 2009; 15: 4137-4142
• 2 De M, Bandeira S, da Fonseca LJ. et al. Oxidative stress as an underlying contributor in the development of chronic complications in diabetes mellitus. Int J Mol Sci 2013; 14: 3265-3284
• 3 Turk Z. Glycotoxines, carbonyl stress and relevance to diabetes and its complications. Physiol Res 2010; 59: 147-156
• 4 Nowotny K, Jung T, Höhn A. et al. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5: 194-222
• 5 Skovso S. Modeling type 2 diabetes in rats using high fat diet and streptozotosin. J Diabetes Invest 2014; 5: 349-358
• 6 Karaağaç N, Salman F, Doğru-Abbasoğlu S. et al. Changes in prooxidant-antioxidant balance in tissues of rats following long-term hyperglycemic status. Endocr Res 2011; 36: 124-133
• 7 Perez Gutierrez RM, Flores Cotera LB, Gonzalez AM. Evaluation of the antioxidant and anti-glycation effects of the hexane extract from Piper auritum leaves in vitro and beneficial activity on oxidative stres and advanced glycation end-product-mediated renal injury in streptozotocin-treated diabetic rats. Molecules 2012; 17: 11897-11919
• 8 Hao HH, Shao ZM, Tang DQ. et al. Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci 2012; 91: 959-967
• 9 Ye HY, Li ZY, Zheng Y. et al. The attenuation of chlorogenic acid on oxidative stres for renal injury in streptozotocin-induced diabetic nephropathy rats. Arch Pharm Res 2016; 39: 989-997
• 10 Sherif IO. Secoisolariciresinol diglucoside in high-fat diet and streptozotocin-induced diabetic nephropathy in rats: a possible renoprotective effect. J Physiol Biochem 2014; 70: 961-969
• 11 Zhang M, Feng L, Gu J. et al. The attenuation of moutan cortex on oxidative stres for renal injury in AGEs-induced mesangial cell dysfunction and streptozotocin-induced diabetic nephropathy rats. Oxid Med Cell Longev 2014; 463815
• 12 Morsy MA, Heeba GH, Mahmoud ME. Ameliorative effect of eprosartan on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats. Eur J Pharmacol 2015; 750: 90-97
• 13 Gao W, Li X, Gao Z. et al. Iron increases diabetes-induced kidney injury and oxidative stress in rats. Biol Trace Elem Res 2014; 160: 368-375
• 14 Tian YM, Guan Y, Li N. et al. Chronic intermittent hypobaric hypoxia ameliorates diabetic nephropathy through enhancing HIF1 signaling in rats. Diabet Res Clin Pract 2016; 118: 90-97
• 15 Figarola JL, Scott S, Loera S. et al. Prevention of early renal disease, dyslipidemia and lipid peroxidation in STZ-diabetic rats by LR-9 and LR-74, novel AGE inhibitors. Diabetes Metab Res Rev 2005; 21: 533-544
• 16 Ciddi V, Dodda D. Therapeutic potential of resveratrol in diabetic complications: In vitro and in vivo studies. Pharmacol Rep 2014; 66: 799-803
• 17 Baye E, Ukropcova B, Ukropec J. et al. de Courten B. Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids 2016; 48: 1131-1149
• 18 Hipkiss AR. Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res 2009; 57: 87-154
• 19 Boldyrev AA, Aldini G, Derave W. Physiology and pathophysiology of carnosine. Physiol Rev 2013; 93: 1803-1845
• 20 Uysal M, Koçak-Toker N, Doğru-Abbasoğlu S. Carnosine protection against liver injury. In: Victor R. Preedy. (ed.). Food and Nutritional Component in Focus No. 8, Imidazole Peptides: Chemistry, Analysis, Function and Effects. London: The Royal Society of Chemistry; 2015: 510-527
• 21 Mong MC, Chao CY, Yin MC. Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Eur J Pharmacol 2011; 653: 82-88
• 22 Kalaz EB, Aydın AF, Doğan-Ekici I. et al. Protective effects of carnosine alone and together with alpha-tocopherol on lipopolysaccharide (LPS) plus ethanol-induced liver injury. Environ Toxicol Pharmacol 2016; 42: 23-29
• 23 Kurata H, Fujii T, Tsutsui H. et al. Renoprotective effects of l-carnosine on ischemia/reperfusion-induced renal injury in rats. J Pharmacol Exp Ther 2006; 319: 640-647
• 24 Soliman KM, Abdul-Hamid M, Othman AI. Effect of carnosine on gentamicin-induced nephrotoxicity. Med Sci Monit 2007; 13: BR73-BR83
• 25 Hasanein P, Teimuri-Far M. Protective effect of bioactive peptide carnosine against lead-induced oxidative stress in kidney of rats. Cell Mol Biol (Noisy-le-grand) 2015; 61: 8-14
• 26 Lee YT, Hsu CC, Lin MH. et al. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 2005; 513: 145-150
• 27 Brown BE, Kim CH, Torpy FR. et al. Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. Atherosclerosis 2014; 232: 403-409
• 28 Pfister F, Riedl E, Wang Q. et al. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell Physiol Biochem 2011; 28: 125-136
• 29 Riedl E, Pfister F, Braunagel M. et al. Carnosine prevents apoptosis of glomerular cells and podocyte loss in STZ diabetic rats. Cell Physiol Biochem 2011; 28: 279-288
• 30 Yay A, Akkuş D, Yapışlar H. et al. Antioxidant effect of carnosine treatment on renal oxidative stress in streptozotocin-induced diabetic rats. Biotechnic Histochem 2014; 89: 552-557
• 31 Peters V, Riedl E, Braunagel M. et al. Carnosine treatment in combination with ACE inhibition in diabetic rats. Regul Pept 2014; 194-195: 36-40
• 32 Wang H, Joseph JA. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 1999; 27: 612-616
• 33 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxidation in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
• 34 Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 1994; 233: 357-363
• 35 Hanasand M, Omdal R, Norheim KB. et al. Improved detection of advanced oxidation protein products in plasma. Clin Chim Acta 2012; 413: 901-906
• 36 Münch G, Keis R, Wessels A. et al. Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur J Clin Chem Clin Biochem 1997; 35: 669-677
• 37 Benzie IFF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 1996; 239: 70-76
• 38 Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61: 882-888
• 39 Mylorie AA, Collins H, Umbles C. et al. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-520
• 40 Worthington V. Catalase. In: Worthington enzyme manual: enzymes and related biochemicals. N. J: Worthington Biochem Corp; 1993: 77-80
• 41 Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium–deficient rat liver. Biochem Biophys Res Commun 1976; 71: 952-958
• 42 Smith PK, Krohn RI, Hermanson GT. et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985; 150: 76-85
• 43 Guo C, Zhang C, Li L. et al. Hypoglycemic and hypolipidemic effects of oxymatrine in high-fat diet and streptozotocin-induced diabetic rats. Phytomedicine 2014; 21: 807-814
• 44 Capeillère-Blandin C, Gausson V, Descamps-Latscha B. et al. Biochemical and spectrophotometric significance of advanced oxidized protein products. Biochim Biophys Acta 2004; 1689: 91-102
• 45 De la Maza MP, Garrido F, Escalante N. et al. Fluorescent advanced glycation end-products (ages) detected by spectro-photofluorimetry, as a screening tool to detect diabetic microvascular complications. J Diabetes Mellitus 2012; 2: 19357-19356
• 46 Aldini G, Orioli M, Rossoni G. et al. The carbonyl scavenger carnosine ameliorates dyslipidemia and renal function in Zucker obese rats. J Cell Mol Med 2011; 15: 1339-1354
• 47 Menini S, Iacobini C, Ricci C. et al. D-Carnosine octylester attenuates atherosclerosis and renal disease in Apo E null mice fed a Western diet through reduction of carbonyl stres and inflammation. Br J Pharmacol 2012; 166: 1344-1356
• 48 Peters V, Schmitt CP, Zschocke J. et al. Carnosine treatment largely prevents alterations of renal carnosine metabolism in diabetic mice. Amino Acids 2012; 42: 2411-2416
• 49 Freedman BL, Hicks PJ, Sale MM. et al. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant 2007; 22: 1131-1135
• 50 Janssen B, Hohenadel D, Brinkkoetter P. et al. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CDNP1. Diabetes 2005; 54: 2320-2327