Diyabetik Sıçanlarda Kemik Dokusunda Lipid Peroksidasyonu ve Antioksidan Sistem Üzerine Losartan’ın Etkileri

Öz

Amaç: Diyabet, kırık riskini artırabilecek osteopeni ve osteoporoz gibi kemik hastalıklarına yol açarken, serbest radikallerin diyabetle ilişkili kemik rezorpsiyonunda önemli rol oynadığı öne sürülmüştür. Anjiyotensin-dönüştürücü enzim inhibitörleri ve anjiyotensin reseptör blokörlerinin diyabetik hastalarda kemik kaybını ve kırılma riskini azaltabilmesi muhtemeldir. Bu nedenle çalışmamız, diyabetik sıçan femurlarında losartanın oksidatif stres ve antioksidan savunma sistemi üzerindeki etkilerini araştırmak ve böylece kemik kalitesindeki bozulmanın olası mekanizmasını açıklamak için tasarlanmıştır.Gereç ve Yöntemler: Sıçanlar dört gruba ayrılmıştır: Kontrol K , diyabet D , losartanla tedavi edilen diyabet D-LOS ve losartanla tedavi edilen kontrol K-LOS . Diyabet, tek doz streptozotosin 50 mg/kg enjeksiyonu ile indüklenmiştir. Diyabetli sıçanlara 8 hafta boyunca 5 mg/kg/gün losartan uygulanmıştır. Kemik dokularında, 2-tiobarbiturik asit reaktif ürünlerinin düzeyi TBARS , süperoksit dismutaz SOD , katalaz KAT ve glutatyon peroksidaz GPx aktiviteleri incelenmiştir.Bulgular: Diyabet uygulaması ile kemik dokuda anlamlı düzeyde artan TBARS değerleri losartan uygulaması ile düşmüştür. Diğer yandan, D grubunda SOD aktivitesi azalırken KAT aktivitesinde bir değişiklik gözlenmemiştir ve losartan tedavisi SOD aktivitesi üzerinde etkili olmamıştır. Diyabet ile birlikte anlamlı düzeyde düşen GPx aktivitesi losartan tedavisi ile normal seviyelerine dönmüştür.Sonuç: Bu bulgular, losartan tedavisinin diyabetik sıçan femurunda oksidatif stresin indüklediği kemik kalitesindeki düşüşü antioksidan enzimlerin modülasyonunu sağlayarak düzeltebileceğini göstermektedir

Anahtar Kelimeler

• Diyabet, Losartan, Oksidatif stres, Antioksidanlar

The Effects of Losartan on Lipid Peroxidation and the Antioxidant System in the Bone Tissue of Diabetic Rats

Abstract

Objective: Diabetes leads to bone disorders such as osteopenia and osteoporosis that can increase the fracture risk and free radicals have been suggested to play significant role in the bone resorption associated with diabetes. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce bone loss and fracture risk in diabetic patients. This study was therefore designed to investigate the effects of losartan on bone quality and the antioxidant defense system in diabetic rat femurs.Material and Methods: The rats were divided into four groups: Control C , diabetes D , losartan-treated diabetes D-LOS and losartan-treated control C-LOS . Diabetes was induced by single injection of streptozotocin 50 mg/kg . The treated rats received 5 mg/kg/day of losartan for 8 weeks. Superoxide dismutase SOD , catalase CAT and glutathione peroxidase GPx activities and 2-thiobarbituric acid reactive substances TBARS levels were analyzed in bone tissue samples.Results: Diabetes revealed a highly significant increase in the TBARS values of rat bones and losartan administration significantly lowered the TBARS levels. SOD activity was decreased in group D but no change in CAT activity was observed and losartan treatment did not affect SOD activity. Diabetes resulted in a marked decrease in GPx that was increased significantly by losartan. Conclusion: These findings indicate that losartan can prevent bone loss and improve the quality of diabetic rat femurs, most probably to reduction of reactive oxygen species and/or modulation of antioxidant enzymes

Keywords

• Diabetes, Losartan, Oxidative stress, Antioxidants

Kaynakça

1. Beam HA, Parsons JR, Lin SS. The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. J Orthop Res 2002; 20(6):1210-6.
2. Lieberman D, Fried V, Castel H, Weitzmann S, Lowenthal MN, Galinsky D. Factors related to successful rehabilitation after hip fracture: A case-control study. Disabil Rehabil 1996; 18(5):224-30.
3. Schwartz AV. Diabetes Mellitus: Does it affect bone? Calcif Tissue Int 2003; 73(6):515-9.
4. Özdemir S. Anjiyotensin II Reseptörünün Deneysel Diyabetik Sıçan Kalbi Elektriksel Aktivitesindeki Rolü. Doktora Tezi. Ankara: Ankara Üniversitesi, 2004.
5. Inzerillo AM, Epstein S. Osteoporosis and diabetes mellitus. Rev Endocr Metab Disord 2004; 5(3):261-8.
6. Keegan TH, Kelsey JL, Sidney S, Quesenberry CP Jr. Foot problems as risk factors of fractures. Am J Epidemiol 2002; 155(10):926-31.
7. Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 2001; 24(7):1192-7.
8. Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR. Older women with diabetes have an increased risk of fracture: A prospective study. J Clin Endocrinol Metab 2001; 86(1):32-8.

9. Reddy GK, Stehno-Bittel L, Hamade S, Enwemeka CS. The biomechanical integrity of bone in experimental diabetes. Diabetes Res Clin Pract 2001; 54(1):1-8.
10. Hamada Y, Kitazawa S, Kitazawa R, Fujii H, Kasuga M, Fukagawa M. Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: A possible role of oxidative stress. Bone 2007; 40(5):1408-14.
11. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31(4):509-19.
12. Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 2004; 314(1):197-207.
13. Chen RM, Wu GJ, Chang HC, Chen JT, Chen TF, Lin YL, Chen TL. 2,6-Diisopropylphenol protects osteoblasts from oxidative stress-induced apoptosis through suppression of caspase-3 activation. Ann N Y Acad Sci 2005; 1042:448-59.
14. Fatokun AA, Stone TW, Smith RA. Hydrogen peroxide- induced oxidative stress in MC3T3-E1 cells: The effects of glutamate and protection by purines. Bone 2006; 39(3): 542-51.
15. Dinh DT, Frauman AG, Johnston CI, Fabiani ME. Angiotensin receptors: Distribution, signalling and function. Clin Sci (Lond) 2001; 100(5): 481-92.
16. Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, Inagami T, Ezura Y, Noda M. Angiotensin II type 2 receptor blockade increases bone mass. J Biol Chem 2009; 284(8):4857-64.
17. Asaba Y, Ito M, Fumoto T, Watanabe K, Fukuhara R, Takeshita S, Nimura Y, Ishida J, Fukamizu A, Ikeda K. Activation of renin-angiotensin system induces osteoporosis independently of hypertension. J Bone Miner Res 2009; 24(2):241-50.
18. Lau T, Carlsson PO, Leung PS. Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia 2004; 47(2):240-8.
19. Inaba S, Iwai M, Furuno M, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M. Role of angiotensin- converting enzyme 2 in cardiac hypertrophy induced by nitric oxide synthase inhibition. J Hypertens 2011; 29(11): 2236-45.
20. Lavoie JL, Sigmund CD. Minireview: Overview of the renin-angiotensin system-an endocrine and paracrine system. Endocrinology 2003; 144(6):2179-83.
21. Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CD. Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 2007; 117(4):1088-95.
22. Gebru Y, Diao TY, Pan H, Mukwaya E, Zhang Y. Potential of RAS inhibition to improve metabolic bone disorders. Biomed Res Int 2013; 932691(10):22-7.
23. De Mello WC, Danser AH. Angiotensin II and the heart: on the intracrine renin-angiotensin system. Hypertension 2000; 35(6):1183-8.
24. Ozdemir S, Tandogan B, Ulusu NN, Turan B. Angiotensin II receptor blockage prevents diabetes-induced oxidative damage in rat heart. Folia Biol 2009; 55(1):11-6.
25. Dinh DT, Frauman AG, Johnston CI, Fabiani ME. Angiotensin receptors: Distribution, signalling and function. Clin Sci 2001; 100(5):481-92.
26. Rejnmark L, Vestergaard P, Mosekilde L. Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: A nationwide case-control study. J Hypertens 2006; 24(3): 581-9.
27. Donmez BO, Ozdemir S, Sarikanat M, Yaras N, Koc P, Demir N, Karayalcin B, Oguz N. Effect of angiotensin II type 1 receptor blocker on osteoporotic rat femurs. Pharmacol Rep 2012; 64(4):878-88.
28. Lynn H, Kwok T, Wong SY, Woo J, Leung PC. Angiotensin converting enzyme inhibitor use is associated with higher bone mineral density in elderly Chinese. Bone 2006; 38(4):584-8.
29. Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R. Angiotensin II accelerates osteoporosis by activating osteoclasts. Faseb J 2008; 22(7):2465-75.
30. Zhang Y, Diao TY, Gu SS, Wu SY, Gebru YA, Chen X, Wang JY, Ran S, Wong MS. Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin. J Renin Angiotensin Aldosterone Syst 2014; 15(3):218-27.
31. Diao TY, Pan H, Gu SS, Chen X, Zhang FY, Wong MS, Zhang Y. Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin- induced type 1 diabetes. J Bone Miner Metab 2014; 32(3): 261-70.
32. Nyman JS, Even JL, Jo CH, Herbert EG, Murry MR, Cockrell GE, Wahl EC, Bunn RC, Lumpkin CK Jr, Fowlkes JL, Thrailkill KM. Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 2011; 48(4):733-40.
33. Kontogiannis J, Burns KD. Role of AT1 angiotensin II receptors in renal ischemic injury. Am J Physiol 1998; 274(1 Pt 2):F79-90.
34. Fang F, Liu GC, Zhou X, Yang S, Reich HN, Williams V, Hu A, Pan J, Konvalinka A, Oudit GY, Scholey JW, John R. Loss of ACE2 exacerbates murine renal ischemia- reperfusion injury. PLoS One 2013; 8(8):e71433.
35. Hamada Y, Fujii H, Kitazawa R, Yodoi J, Kitazawa S, Fukagawa M. Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia: A novel role of oxidative stress and therapeutic implications. Bone 2009; 44(5):936-41.
36. Nakhaee A, Bokaeian M, Akbarzadeh A, Hashemi M. Sodium tungstate attenuate oxidative stress in brain tissue of streptozotocin-induced diabetic rats. Biol Trace Elem Res 2010; 136(2):221-31.
37. Blakytny R, Spraul M, Jude EB. Review: The diabetic bone: A cellular and molecular perspective. Int J Low Extrem Wounds 2011; 10(1):16-32.
38. Aydemir M, Ozturk N, Dogan S, Aslan M, Olgar Y, Ozdemir S. Sodium tungstate administration ameliorated diabetes-induced electrical and contractile remodeling of rat heart without normalization of hyperglycemia. Biol Trace Elem Res 2012; 148(2):216-23.
39. Wasowicz W, Neve J, Peretz A. Optimized steps in fluorometric determination of thiobarbituric acid-reactive substances in serum: Importance of extraction pH and influence of sample preservation and storage. Clin Chem 1993; 39(12):2522-6.
40. Johansson LH, Borg LA. A spectrophotometric method for determination of catalase activity in small tissue samples. Anal Biochem 1988; 174(1):331-6.
41. Mannervik B. Glutathione peroxidase. Methods Enzymol 1985; 113:490-5.
42. Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications 2010; 24(5):334-44.
43. Liang W, Luo Z, Ge S, Li M, Du J, Yang M, Yan M, Ye Z. Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia. Eur J Pharmacol 2011; 670(1):317-24.
44. Ivanov M, Mihailovic-Stanojevic N, Grujic Milanovic J, Jovovic D, Markovic-Lipkovski J, Cirovic S, Miloradovic Z. Losartan improved antioxidant defense, renal function and structure of postischemic hypertensive kidney. PLoS One 2014; 9(5):e96353.
45. Behl T, Kotwani A. Potential of angiotensin II receptor blockers in the treatment of diabetic retinopathy. Life Sci 2017; 176:1-9.
46. Blakely PK, Huber AK, Irani DN. Type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice. J Neuroinflammation 2016; 13(1):196.
47. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II- mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996; 97(8):1916-23.
48. Queiroz-Junior CM, Silveira KD, de Oliveira CR, Moura AP, Madeira MF, Soriani FM, Ferreira AJ, Fukada SY, Teixeira MM, Souza DG, da Silva TA. Protective effects of the angiotensin type 1 receptor antagonist losartan in infection-induced and arthritis-associated alveolar bone loss. J Periodontal Res 2015; 50(6):814-23.
49. Chen S, Grover M, Sibai T, Black J, Rianon N, Rajagopal A, Munivez E, Bertin T, Dawson B, Chen Y, Jiang MM, Lee B, Yang T, Bae Y. Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton. Mol Genet Metab 2015; 115(1):53-60.
50. Pieper GM, Jordan M, Dondlinger LA, Adams MB, Roza AM. Peroxidative stress in diabetic blood vessels. Reversal by pancreatic islet transplantation. Diabetes 1995; 44(8): 884-9.
51. Baud O, Greene AE, Li J, Wang H, Volpe JJ, Rosenberg PA. Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes. J Neurosci 2004; 24(7):1531-40.
52. Kljai K, Runje R. Selenium and glycogen levels in diabetic patients. Biol Trace Elem Res 2001; 83(3):223-9.
53. Gur S. Effects of sodium selenate treatment on altered responses of left and right atria from streptozotocin- induced diabetic rats. J Cardiovasc Pharmacol 2004; 44(1):9-15.