اثر محافظتی نانواکسید منیزیم در آسیب ایسکمی/رپرفیوژن کلیه بر عملکرد کلیه و فاکتور رشد اندوتلیال عروقی (VEGF) در موش‌صحرایی نر
محورهای موضوعی : فصلنامه زیست شناسی جانوری
مرضیه مینایی
1
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اکرم عیدی
2
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,
پژمان مرتضوی
3
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احمد اصغری
4
1 - گروه زیست شناسی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
2 - گروه زیست شناسی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
3 - گروه پاتولوژی دامپزشکی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
4 - گروه علوم درمانگاهی، واحد علوم و تحقیقات، دانشگاه آزاد اسلامی، تهران، ایران
کلید واژه: نانواکسید منیزیم, ایسکمی/رپرفیوژن, کلیه, VEGF,
چکیده مقاله :
آسیب ایسکمی/پرفیوژن مجدد (I/R) با محدود شدن خون‌رسانی به اندام و به‌دنبال آن بازگشت جریان خون و اکسیژن‌رسانی مجدد مشخص می‌شود. هدف از این مطالعه، سنجشاثر محافظتی نانواکسیدمنیزیم (MgO) در آسیب ایسکمی/رپرفیوژن کلیه بر عملکرد کلیوی و فاکتور رشد اندوتلیال عروقی (VEGF) در موش‌صحرایی نر می‌باشد. در این مطالعه 54 سر موش صحرایی نر بالغ نژاد ویستار به‌طور تصادفی به 9 گروه 6 تایی شامل گروه‌های کنترل سالم، شاهد، کنترل I/R، سه گروه تجربی سالم و سه گروه تجربیI/R تقسیم شدند. القای آسیب I/R از طریق بستن پدیکل کلیوی چپ به مدت 20 دقیقه ایجاد شد. حیوانات با استفاده از MgO (دوزهای 25/1، 5/2 و 5 میلی‌گرم/کیلوگرم) به‌مدت 30 روز از طریق گاواژ مورد آزمایش قرار گرفتند و در نهایت نمونه‌های سرم برای بررسی عملکرد کلیه جمع‌آوری شد. به‌علاوه با قربانی‌شدن حیوانات، بافت کلیه برای بررسی ایمونوهیستوشیمی میزان بیان VEGF اخذ شد و داده‌هاي حاصل مورد آنالیز آماري قرارگرفت (05/0 >p ). نتایج نشان داد که موش‌های I/R که با نانواکسید منیزیم مداخله شدند،در غلظت‌های 5/2 و 5 میلی‌گرم/کیلوگرم سطوح اوره و کراتینین سرم را به‌طور معنی‌داری کاهش دادند. همچنین عملکرد کلیوی و بیان VEGF، بهبود معنی‌داری نشان داد. MgO توانسته به‌عنوان یک وازودیلاتور قوی، سطوح اوره و کراتینین سرم را به‌عنوان شاخص‌های آسیب سلول‌های کلیوی، در گروه‌های I/R، بهبود بخشد. همچنین با کاهش سطح بیان VEGF در گروه‌های تحت درمان MgO، ممکن است نانواکسیدمنیزیم برای محافظت از هیپوکسی ناشی‌از آسیب I/R به‌طور مؤثری واسطه شود.
Ischemia/reperfusion (I/R) injury is characterized by the restriction of blood supply to the organ followed by the return of blood flow and reoxygenation. The aim of this study was to measure Protective effect of nano magnesium oxide (MgO) on I/R on renal function and vascular endothelial growth factor (VEGF) in male Wistar rats. In this study, 54 adults male Wistar rats were randomly divided into 9 groups of 6 rats, including healthy control, control, I/R control, three healthy experimental groups, and three I/R experimental groups. I/R injury was induced by ligation of the left renal pedicle for 20 minutes. Animals were tested using MgO (doses of 1.25, 2.5 and 5 mg/kg) for 30 days via gavage and finally serum samples were collected to assess renal function. In addition, after sacrificing the animals, kidney tissue was obtained for immunohistochemical examination of VEGF expression and the resulting data were statistically analyzed (p<0.05). The results showed that I/R mice that were intervened with MgO significantly reduced serum urea and creatinine levels at concentrations of 2.5 and 5 mg/kg. Renal function and VEGF expression also showed significant improvement. MgO, as a potent vasodilator, were able to improve serum urea and creatinine levels as indicators of renal cell damage in I/R groups. Also, by reducing the expression level of VEGF in MgO-treated groups, MgO may effectively mediate the protection against hypoxia induced by I/R injury.
1. Neuwelt EA, Hamilton BE, Varallyay CG, Rooney WR, Edelman RD, Jacobs PM, Watnick SG. Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?. Kidney Int. 2009;75(5): 465-474.
2. Brede CH, Labhasetwar V. Applications of Nanoparticles in the Detection and Treatment of Kidney Diseases. Adv Chronic Kidney Dis. 2013;20(6):454-465.
3. Badawy MM, Sayed-Ahmed MZ, Almoshari Y, Alqahtani SS, Alshahrani S, Mabrouk HAA, Abd-Elsalam MM, Alkashif K, Ahmad S, El-Sebaey AM, Hamama MG, Moustafa Ahmed DA. Magnesium Supplementation Alleviates the Toxic Effects of Silica Nanoparticles on the Kidneys, Liver, and Adrenal Glands in Rats. Toxics. 2023;11(4):381.
4. Vask A, Titma T, Visnapuu M, Vija H, Kakinen A, Sihtmae M, Pokhrel S, Madler L, Heinlaan M, Kisand V, Shimmo R, Kahru A. Toxicity of 11 Metal Oxide Nanoparticles to Three Mammalian Cell Types In Vitro. Curr. Top. Med. Chem. 2015;15(18):1914-1929.
5. Kim BS, Goligorsky MS. Role of VEGF in kidney development, microvascular maintenance and pathophysiology of renal disease. Korean J Intern Med. 2003;18(2): 65-75.
6. Vidic J, Stankic S, Haque F, Ciric D, Goffic RL, Vidy A, Jupille J, Delmas B. Selective antibacterial effects of mixed ZnMgO nanoparticles. J. Nanoparticle Res. 2013;15(5): 1595–1604.
7. Hajimiresmaiel J, Davoodi H, Namazi N, Javedan GH, Pazoki-Toroudi H, Ajami M. Effect of omega 3 fatty acids on oxidative stress in acute renal failure induced by ischemia reperfusion. Iran J Nutr Sci Food Technol. 2014;8(4): 155-162. [In Persian]
8. Kumar G, Solanki MH, Xue X, Mintz R, Madankumar S, Chatterjee PK, Metz CN. Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 2017;313(2):339-350.
9. Kumaran RS, Choi YK, Singh V, Song HJ, Song KG, Kim KJ, Kim HJ. In vitro cytotoxic evaluation of MgO nanoparticles and their effect on the expression of ROS genes. Int. J. Mol. Sci. 2015;16(4):7551-7564.
10. Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. J. Inorg. Biochem. 2009;130(1):41-50.
11. Jahangiri L, Kesmati M, Najafzadeh H. Evaluation of analgesic and anti-inflammatory effect of nanoparticles of magnesium oxide in mice with and without ketamine. Eur. Rev. Med. Pharmacol. Sci. 2013;17(20):2706-2710.
12. Kellum JA, Unruh M.L, Murugan R. Acute kidney injury. BMJ clinical evidence, Published online 2011 Mar 28.
13. Jin T, He Y. Antibacterial activities of magnesium oxide (MgO) nanoparticles against foodborne pathogens. J. Nanopart. Res. 2011;13(12):6877-6885.
14. Revell PA. The biological effects of nanoparticles. Nanotechnol. Percept. 2006; 2(1):283-298.
15. Sinha MK. Role of ‘Ischemia-modified albumin’, a new biochemical marker of myocardial ischemia, in the early diagnosis of acute coronary syndromes. Emerg. Med. 2004; 21(1):29-34.
16. Bonventre JV. Mechanisms of ischemic acute renal failure. Kidney int. 1993;43(5): 1160-1178.
17. Padanilam BJ. Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis. Am. J. Physiol. Renal Physiol. 2003;284(4):608-627.
18. Vetterlein F, Bludau J, Petho-Schramm A, Schmidt G. Reconstruction of blood flow distribution in the rat kidney during postischemic renal failure. Nephron. 1994;66(2):208-214.
19. Legrand M, Mik EG, Johannes T, Payen D, Ince C. Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol. Med. 2008;14(7-8):502-516.
20. Onorati F, Rubino AS, Nucera S, Foti D, Sica V, Santini F, Gulletta E, Renzulli A. Off-pump coronary artery bypass surgery versus standard linear or pulsatile cardiopulmonary bypass: endothelial activation and inflammatory response. Eur J Cardiothorac Surg. 2010;37(4):897-904.
21. Collard CD, Gelman S. Pathophysiology, clinical manifestations and prevention of ischemiareperfusion injury. Anesthesiol. J. 2001;94(6):1133-1138.
22. Tsutsui H, Sugiura T, Hayashi K, Ohkita M, Takaoka M, Yukimura T, Matsumura Y. Moxonidine prevents ischemia/reperfusion-induced renal injury in ratsEur. J. Pharmacol. 2009;603(1-3):73-78.
23. Dzietko M, Derugin N, Wendland MF, Vexler ZS, Ferriero D.M. Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl. Stroke Res. 2013;4(2):189-200.
24. Holzer LA, Cör A, Pfandlsteiner G, Holzer G. Expression of VEGF, its receptors, and HIF-1alpha in Dupuytren’s disease. Acta Orthop. 2013;84(4):420-425.
25. Ghavamipour F, Shahangian SH, Sajedi R., Arab SH, Mansouri K, Aghamaali MR. Development of a highly‐potent anti‐angiogenic VEGF8–109 heterodimer by directed blocking of its VEGFR‐2 binding site. FEBS J. 2014;281(19):4479-4494.
26. Sousa Moreira IP. Alexandrino Fernandes, and M. Joao Ramos, Vascular endothelial growth factor (VEGF) inhibition-a critical review. Anti-Cancer Agents in Med. Chem. 2007;7(2):223-245.
27. Crawford Y, Ferrara N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res. 2009;335(1):261-269.
28. Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. The oncologist. 2004;9(1):2-10.
29. Costache MI. Ioana M, Iordache S, Ene D, Costache CA, Săftoiu A. VEGF expression in pancreatic cancer and other malignancies: a review of the literature. Rom. J. Intern. Med. 2015;53(3):199-208.
30. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat. Rev. Cancer. 2002;2(10):795-803.
31. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat. Rev. Clin. Oncol. 2009;6(10):569-579.
32. Liu Y, Guo Y, Wang Z, Nie W. Effects of source and level of magnesium on catalase activity and its gene expression in livers of broiler chickens. Arch. Anim. Nutr. 2007;61(4):292-300.
33. Wei CC, Wu K, Gao Y, Zhang LH, Li DD, Luo Z. Magnesium Reduces Hepatic Lipd Accumulation in Yellow Catfish (Pelteobagrusfulvidraco) and Modulates Lipogenesis and Lipolysis via PPARA, JAK-STAT, and AMPK Pathways in Hepatocytes. J. Nutr. 2017;47(6):1070-1078.
34. Asghari A, Jamshidi N, Neshat M.. Serologic evaluation of the effect of administration of magnesium sulfate on the subsequent renal function Induction of reperfusion ischemia in rats. Comparative Pathobiology. Sci. Res. J. 2016;13(1):1805-1812.
35. Chien CH, Lee P, Chen CH, Ma M, Lai M, Hsu S. De Novo Demonstration and Co-localization of Free-Radical Production and Apoptosis Formation in Rat Kidney Subjected to Ischemia/Reperfusion. ASN and JASN. 2001;12(5):973-982.
36. Kesmati M, Konani M, Torabi M, Khajehpour L. Magnesium oxide nanoparticles reduce anxiety induced by morphine withdrawal in adult male mice. Physiol. Pharmacol. 2016;20(3):197-205.
37. Mangalampalli B, Dumala N, Perumalla Venkata R, Grove P. Genotoxicity, biochemical, and biodistribution studies ofmagnesium oxide nano and microparticles in albino wistar ratsafter 28-day repeated oral exposure. Environ. Toxicol. 2018;33(4):396-410.
38. Taheri YA, Neshat M, Garjani A Doustar NY. Study the effects of metformin on renal function and structure after unilateral ischemia-reperfusion in rat. Res Pharm Sci. 2012;7(5):77.
39. Asgari M, Hafezi Ahmadi MR. Value of Immunohistochemistry in Comparison to Immofluorescence for Detecting Immune Deposits in renal Biopsy. Iran. J. Med. Sci. 2007;14(55):141-148. [In Persian]
40. Dabbs DJ. Diagnostic Immunohistochemistry, 5th Edition, Elsevier. 2019.
41. Almond PS, Matas AJ, Gillingham K, Dunn DL, Payne WD, Gores P, Gruessner R, Najarian JS. Predictors of chronic rejection in renal transplant recipients. Transplant. Proc. 1993;25(1-2):936.
42. Baker GL, Corry RJ, Autor AP. Oxygen free radical induced damage in kidneys subjected to warm ischemia and reperfusion. Protective effect of superoxide dismutase. Ann. Surg. 1985;202(5):628-641.
43. Tietz NW. Clinical guide to laboratory tests. 3 th ed. Philadelphia: WB Saunders Co. 1995; pp:22-23.
44. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat. Rev. 1999;25(1):47-58.
45. Lippi G, Montagnana M, Guidi GC. Albumin cobalt binding and ischemia modified albumin generation: an endogenous response to ischemia?. Int. J. Cardiol. 2006;108(3):410– 411.
46. Moeini-Nodeh S, Rahimifard M, Baeeri M, Abdollahi M. Functional Improvement in Rats' Pancreatic Islets Using Magnesium Oxide Nanoparticles Through Antiapoptotic and Antioxidant Pathways. Biol Trace Elem Res. 2017;175(1):146-155.
47. Pundir M, Arora S, Kaur T, Singh Pal R, Singh A. Effect of modulating the allosteric sites ofN-methyl-D-aspartate receptors in ischemia-reperfusioninduced acute kidney injury. J Surg Res. 2013;183(2):668-677.
48. Shi LE, Xing L, Hou B, Ge H, Guo X, Tang ZH. Inorganic nano mental oxides used as antimicroorganism agents for pathogen control, current research. Technol Edu Topics. 2010; 2010:361-368.
49. Paller MS. The cell biology of reperfusion injury in the kidney. J. INVEST MED. 1994;42(4):632-639.
50. Choi EK, Jung H, Kwak KH, Yi SJ, Lim JA, Park SH, Park JM, Kim S, Jee D, Lim DG. Inhibition of Oxidative Stress in Renal Ischemia- Reperfusion Injury. Anesth Analg. 2017;124(1):204-213.
51. Horibata K, Tanoue A, Ito M, Takemura Y. Relationship between renal function and serum magnesium concentration in elderly outpatients treated with magnesium oxide. Geriatr Gerontol Int. 2016;16(5):600-605
52. Nath KA, Norby SM. Reactive oxygen species and acute renal failure. Am. J. Med. 2000;109(8):65-78.
53. Zhao ZH, Tang ZH, Zhang W, Liu J, Li B. Magnesium isoglycyrrhizinate protects against renal ischemia reperfusion injury in a rat model via anti inflammation, anti oxidation and anti apoptosis. Mol. Med. Rep. 2017,16(3):3627-3633.
54. Sousa Moreira I, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition-a critical review. Anti-Cancer Agents in Med. Chem. 2007; 7(2):223-245.
55. Gozal D, Lipton AJ, Jones KL. Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea. Sleep. 2002; 25(1):59-65.
56. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med. 2002;165(1):67-70.
57. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359(6398):843-845.
58. Chen L, Wu F, Xia WH, Zhang YY, Xu SY, Cheng F, Liu X, Zhang XY, Wang SM, Tao J. Gene transfer contributes to in vivo reendothelialization capacity of endothelial progenitor cells. Cardiovasc. Res. 2010;88(3):462-470.
59. Kwon O, Miller S, Li N, Khan A, Kadry Z, Uemura T. Bone marrow-derived endothelial progenitor cells and endothelial cells may contribute to endothelial repair in the kidney immediately after ischemia-reperfusion. J Histochem Citochem. 2010; 58(8):687-694.
60. Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circ. 2003;07(8):1164-1169.
61. Yu Y, Gao Y, Qin J, Kuang CY, Song MB, Yu SY, Cui B, Chen JF, Huang L. Promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury. Basic Res Cardiol. 2010;105(6):713-724.
62. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989; 246(4935):1306-1309.
63. Rajnoch A, Lodererova A, Szabo, E, Honsova A, Vannay S, Bloudickova I, Viklicky OM. Regulators of Angiogenesis in Renal Ischemia/Reperfusion Injury in Normotensive and Hypertensive Rats: Effect of Tacrolimus. Transplant Proc. 2005;37(1):352-354.
64. Zhou R, Liu H, Hou X, Liu Q, Sun SH, Li W, Cao W, Nie W, Shi CH, Chen W. Bi-functional KIT-PR1P peptides combine with VEGF to protect ischemic kidney in rats by targeting to Kim-1. Regen. Ther. 2024;25(1):162-173.