Reno-protective effects of GLP-1 receptor agonist and anti-platelets in experimentally induced diabetic kidney disease in male albino rats

Document Type : Original Article

Authors

1 Physiology Department, Faculty of Medicine, Fayoum University, Fayoum, Egypt

2 Professor of Physiology, Physiology Department, Faculty of Medicine, Azhar University. Cairo, Egypt

3 Professor of Biochemistry, Biochemistry and Molecular Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt

4 Histology Department, Faculty of Medicine, Fayoum University, Fayoum, Egypt

Abstract

Objective(s): The prevalence of chronic kidney disease in diabetics is progressively increasing with an increased risk of fatal complications. 
Materials and Methods: Sixty male albino rats were used in the study, and type 2 diabetes mellitus were induced. Diabetic rats were divided randomly into 5 groups, the control diabetic group and 4 treated groups were treated with metformin (group3), dulaglutide (group 4), metformin & cilostazol (group 5), and the last group was treated with dulaglutide & cilostazol (group 6).  At the end of the experiment, the weight of rats and systolic blood pressure were estimated. After overnight fasting, the serum levels of blood glucose, lipid profile, and kidney function were measured. After scarification, gene expression of eNOS and NFKB in kidney tissue were estimated and kidney tissues were examined for histopathology. 
Results: Diabetic rats showed a significant increase in body weight, blood pressure, serum blood glucose, lipid profile, and impaired kidney function. Metformin and dulaglutide are associated with a significant decrease in blood pressure, blood glucose level, serum lipid profile, and improved kidney function. These changes are associated with a significant increase in anti-oxidative markers, and decreased inflammatory and fibrotic markers, especially with the addition of cilostazol. 
Conclusion: Metformin and dulaglutide have been shown to ameliorate kidney damage in diabetics by stimulating the anti-oxidant defense system, normalizing kidney functional parameters, and improving histopathological changes. The addition of cilostazol to metformin or dulaglutide increased some of their anti-oxidants and anti-inflammatory properties.

Keywords

References

1. Wang B, Liu L, Qiao D, Xue Y, Liu X, Zhang D, et al. The association between frequency of away-from home meals and type 2 diabetes mellitus in rural Chinese adults: the Henan Rural Cohort Study. Eur J Nutr 2020; 59: 3815-3825.
2. Trinh MD, Plihalova A, Gojda J, Westlake K, Spicka J, Lattova Z, et al. Obstructive sleep apnoea increases lipolysis and deteriorates glucose homeostasis in patients with type 2 diabetes mellitus. Sci Rep 2021; 11: 3567-3575.
3. Singh S, Sonkar SK, Sonkar GK, Mahdi AA. Diabetic kidney disease: A systematic review on the role of epigenetics as diagnostic and prognostic marker. Diabetes Metab Res Rev. 2019; 35:e3155. 
4. Yasuda-Yamahara M, Kume S, Maegawa H. Roles of mTOR in Diabetic Kidney Disease. Anti-oxidants 2021; 10:321-329.
5. Ilyas Z, Chaiban JT, Krikorian A. Novel insights into the pathophysiology and clinical aspects of diabetic nephropathy. Rev Endocr Metab Disord 2017; 18: 21-28.
6. Ding Y, Xu M, Lu Q, Wei P, Tan J, Liu R. Combination of honey with metformin enhances glucose metabolism and ameliorates hepatic and nephritic dysfunction in STZ-induced diabetic mice. Food Funct 2019; 10: 7576-7587.
7. Lin CX, Li Y, Liang S, Tao J, Zhang LS, Su YF, et al. Metformin attenuates cyclosporine a-induced renal fibrosis in rats. Transplantation 2019; 103: e285-e296.
8. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab 2018; 27: 740-756.
9. Pandya M, Parmar C, Singh M. Study of prothrombin time and activated partial thromboplastin time in type II diabetes mellitus. International Journal of Clinical and Diagnostic Pathology 2020; 3: 173-175.
10. Chian CW, Lee YS, Lee YJ, Chen YH, Wang CP, Lee WC, et al. Cilostazol ameliorates diabetic nephropathy by inhibiting highglucose- induced apoptosis. Korean J Physiol Pharmacol 2020; 24: 403-412.
11. Y. Si, Y. Zhao, H. Hao et al., “Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetes rats: Identification of a novel role in improving insulin sensitivity,” Diabetes, 2012, pp. 1616–1625. 
12. Zhang S, Xu H, Yu X, Wu YI, Sui D. Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes. Exp Ther Med 2017; 14: 383-390.
13. Tuttle KR, McKinney TD, Davidson JA, Anglin G, Harper KD, Botros FT. Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. Diabetes Obes Metab 2017; 19: 436-441.
14. Abdel-Aziz AM, Rifaai RA, Abdel-Gaber SA. Possible mechanisms mediating the protective effect of cilostazol in L-arginine induced acute pancreatitis in rats: role of cGMP, cAMP, and HO-1. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393: 1859-1870.
15. El-mosallamy AE., Sleem AA., Abdel-Salam OM., Shaffie N. and Kenawy SA Antihypertensive and cardioprotective effects of pumpkin seed oil. J Med Food 2012; 15: 180-189.
16. Chen N, Mu L, Yang Z, Du C, Wu M, Song S, et al. Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy. J Cell Physiol 2021; 236: 625-640.
17. Lyseng-Williamson KA. Glucagon-like peptide-1 receptor analogues in type 2 diabetes: their use and differential features. Clin Drug Investig 2019; 39: 805-819.
18. Veneti S, Tziomalos K. Is there a role for glucagon-like peptide-1 receptor agonists in the management of diabetic nephropathy? World J Diabetes 2020; 11: 370-373.
19. Derosa G, Gaudio G, D’Angelo A, Maffioli P. Efficacy of Berberis aristata Compared with Metformin in Improving Glycemic Control and Insulin Resistance in Patients with Type 2 Diabetes Mellitus. J Food Nutr Res 2020; 8: 212-215.
20. Figueiredo ID, Lima TFO, Inácio MD, Costa MC, Assis RP, Brunetti IL, et al. Lycopene improves the metformin effects on glycemic control and decreases biomarkers of glycoxidative stress in diabetic rats. Diabetes Metab Syndr Obes 2020; 13: 3117-3135.
21. Wang J, Li HQ, Xu XH, Kong XC, Sun R, Jing T, et al. The effects of once-weekly dulaglutide and insulin glargine on glucose fluctuation in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus. BioMed Res Int 2019; 2019: 2682657.
22. Greco EV, Russo G, Giandalia A, Viazzi F, Pontremoli R, De Cosmo S. GLP-1 Receptor Agonists and Kidney Protection. Medicina (Kaunas). 2019; 55: 233-246.
23. Tuttle KR, McGill JB. Evidence‐based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease. Diabetes Obes Metab 2020; 22: 1014-1023.
24. Pilatti LD, Rodrigues R, Nascimento ND, Gomes ML, Zanin SM, Farago PV, et al. Effect of cilostazol-loaded PCL/PEG nanocapsules on abdominal aortic tunics and lipid profile of wistar rats. Braz Arch Biol Technol 2020; 63: e20200062.
25. Su SC, Hung YJ, Huang CL, Shieh YS, Chien CY, Chiang CF, et al. Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways. J Biomed Sci 2019; 26: 68-80.
26. Gajos G, Siniarski A, Natorska J, Ząbczyk M, Siudut J, Malinowski KP, et al. Polyhedrocytes in blood clots of type 2 diabetic patients with high cardiovascular risk: Association with glycemia, oxidative stress and platelet activation. Cardiovasc Diabetol. 2018; 17:146-156.
27. Heeba GH, El-Deen RM, Abdel-Latif RG, Khalifa MMA. Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: A comparative study. Can J Physiol Pharmacol 2020; 98: 498-505.
28. Mostafa DK, Khedr MM, Barakat MK, Abdellatif AA, Elsharkawy AM. Autophagy blockade mechanistically links proton pump inhibitors to worsened diabetic nephropathy and aborts the renoprotection of metformin/enalapril. Life Sci 2021; 265: 118818.
29. Leon-Jimenez D, Usategui RM, Obregón FM, Aragón LM, Carmona MD, Garrido TG, et al. Dulaglutide preserves kidney function and maintains metabolic control at a 36-month follow-up. Authorea Preprints 2020; https://www.authorea.com/users/313156/articles/443750.
30. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 7: 776-785. 
31. Zhang L, Su S, Zhu Y, Guo J, Guo S, Qian D, et al. Mulberry leaf active components alleviate type 2 diabetes and its liver and kidney injury in db/db mice through insulin receptor and TGF-β/Smads 
signaling pathway. Biomed Pharmacother 2019; 112: 108675. 
32. Huang S, Tan M, Guo F, Dong L, Liu Z, Yuan R, et al. Nepeta angustifolia C. Y. Wu improves renal injury in HFD/STZ-induced diabetic nephropathy and inhibits oxidative stress-induced apoptosis of mesangial cells. J Ethnopharmacol. 2020; 255: 112771.
33. Ragab D, Abdallah DM, El-Abhar HS. Cilostazol renoprotective effect: Modulation of PPAR-γ, NGAL, KIM-1 and IL-18 underlies its novel effect in a model of ischemia-reperfusion. PLoS One 2014; 9: e95313.
34. Rashad AM, Heeba GH, Hamad SH. Age-dependent Role of Cilostazol on Cold Restraint Stress induced Gastric Ulceration in Female Rats. J Clin Exp Invest 2019; 10:  em00728.
35. Yi H, Huang C, Shi Y, Cao Q, Chen J, Chen XM, et al. Metformin attenuates renal fibrosis in a mouse model of adenine-induced renal injury through inhibiting tgf-β1 signaling pathways. Front Cell Dev Biol 2021; 9: 603802.
36. Park HJ, Han H, Oh EY, Kim SR, Park KH, Lee JH, et al. Empagliflozin and dulaglutide are effective against obesity-induced airway hyperresponsiveness and fibrosis in a murine model. Sci Rep 2019; 9: 15601-15608.
37. Park JH, Choi BH, Ku SK, Kim DH, Jung KA, Oh E, et al. Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin. Arch Pharm Res 2017; 40: 391-402.
38. Xu J, Liu LQ, Xu LL, Xing Y, Ye S. Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis. Clin Exp Pharmacol Physiol 2020; 47: 599-608.
39. Ren H, Shao Y, Wu C, Ma X, Lv C, Wang Q. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Mol Cell Endocrinol 2020; 500: 110628.
40. Sofogianni A, Filippidis A, Chrysavgis L, Tziomalos K, Cholongitas E. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J Hepatol 2020; 12: 493-505.
41. Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, et al. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biology 2019; 20:247-260.
42. Pan Q, Lu X, Zhao C, Liao S, Chen X, Guo F, et al. Metformin: the updated protective property in kidney disease. Aging (Albany NY) 2020; 12: 8742-8759.
43. Nie XQ, Chen HH, Zhang JY, Zhang YJ, Yang JW, Pan HJ, et al. Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways. Acta Pharmacol Sin 2016; 37: 483-4896.
44. Jeddi S, Gheibi S, Carlström M, Kashfi K, Ghasemi A. Long-term co-administration of sodium nitrite and sodium hydrosulfide inhibits hepatic gluconeogenesis in male type 2 diabetic rats: Role of PI3K-Akt-eNOS pathway. Life Sci 2021; 265: 118770. 
45. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab 2021; 46: 101102.
46. Xiong QF, Fan SH, Li XW, Niu Y, Wang J, Zhang X, et al. GLP-1 relaxes rat coronary arteries by enhancing ATP-sensitive potassium channel currents. Cardiol Res Pract 2019; 2019: 1968785.
47. Sharaf El Din UA, Salem MM, Abdulazim DO. Time to prevent the development of diabetic nephropathy in both type 1 and type 2 diabetic patients. J Clin Nephrol Kidney Dis 2019; 4: 1023.
48. Nna VU, Abu Bakar AB, Ahmad A, Eleazu CO, Mohamed M. Oxidative stress, NF-κB-mediated inflammation and apoptosis in the testes of streptozotocin-induced diabetic rats: Combined protective effects of malaysian propolis and metformin. Anti-oxidants (Basel) 2019; 8: 465-287.
49. Li P, Bukhari SN, Khan T, Chitti R, Bevoor DB, Hiremath AR,                                                                                              
et al. Apigenin-loaded solid lipid nanoparticle attenuates diabetic nephropathy induced by streptozotocin nicotinamide through Nrf2/HO-1/NF-kB signalling pathway. Int J Nanomedicine 2020; 
15: 9115-9124.
50. He P, Kawamura H, Takemoto M, Maezawa Y, Ishikawa T, Ishibashi R, et al. Combination of cilostazol and probucol protected podocytes from lipopolysaccharide-induced injury by both anti-inflammatory and anti-oxidative mechanisms. J Nephrol 2017; 30: 531-541. 
51. Furuichi K, Shimizu M, Okada H, Narita I, Wada T. Clinico-pathological features of kidney disease in diabetic cases. Clin Exp Nephrol 2018; 22: 1046-1051.
52. Fang Y, Li F, Qi C, Mao X, Wang F, Zhao Z, et al. Metformin effectively treats Tsc1 deletion-caused kidney pathology by upregulating AMPK phosphorylation. Cell Death Discovery 2020; 6: 1-6.
53. Kim S, Kang SW, Joo J, Han SH, Shin H, Nam BY, et al. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 2021; 12:160-173.
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 12
December 2022
Pages 1487-1497

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