Effect of aminoguanidine on plasminogen activator inhibitor-1 and receptor of advanced glycation endproduct in the liver of streptozotocin-induced diabetic rats
Abstract
Objectives: Advanced glycation end products (AGEs) play an important role in the development and progression of diabetic complications. The receptor for AGE (RAGE) is the ligand-binding site of AGE that initiates and accelerates the atherosclerotic process. Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic factor that has been proposed as a biological marker for prognostic assessment, monitoring of microvascular and macrovascular complications in diabetes. The purpose of this study is to investigate the effects of aminoguanidine on RAGE and PAI-1 expression levels in the liver of streptozotocin-induced diabetic rats.
Methods: Diabetes was induced in rats by intraperitoneal injection of streptozocin (STZ, 50 mg/kg). On day 3, diabetic rats were administered 50, 100, and 200 mg/kg/day of aminoguanidine. The expression of PAI-1 and RAGE in the liver tissue was evaluated using real-time PCR.
Results: PAI-1 and RAGE gene expression levels were higher in the liver of the diabetic rats compared to the control group. Aminoguanidine at 50, 100, and 200 mg/kg decreased PAI-1 and RAGE gene expression in the liver (p<0.001 at all doses). However, these genes were downregulated only at a dose of 200 mg/kg in healthy rats (p<0.0001). In addition, hepatic AGE protein levels were significantly decreased following treatment of the diabetic rats with aminoguanidine (p<0.001). There was also a significant correlation between AGE protein concentration and the expression of PAI-1 and RAGE.
Conclusion: In summary, the data of the present study suggest that aminoguanidine reduced the expression of PAI-1 and RAGE in the liver of the diabetic rats.
2. Bahramzadeh, A., K. Bolandnazar, and R. Meshkani, Resveratrol as a potential protective compound against skeletal muscle insulin resistance. Heliyon, 2023.
3. Teimouri, M., H. Hosseini, Z. ArabSadeghabadi, R. Babaei-Khorzoughi, S. Gorgani-Firuzjaee, and R. Meshkani, The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications. Journal of physiology and biochemistry, 2022: p. 1-16.
4. Taghizadeh, N., S. Mohammadi, V. Saeedi, L. Haghighi, M. Nourbakhsh, M. Nourbakhsh, et al., Association between Steroid Hormones and Insulin Resistance in Patients with Polycystic Ovary Syndrome. Acta Biochimica Iranica, 2023. 1(1): p. 26-31.
5. Inzucchi, S.E., Diagnosis of diabetes. N Engl J Med, 2013. 368(2): p. 193.
6. Rowan, S., E. Bejarano, and A. Taylor, Mechanistic targeting of advanced glycation end-products in age-related diseases. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2018. 1864(12): p. 3631-3643.
7. Shiri, H., A. Karimpour, M. Sattari, S. Hemmati, S. Seyyedebrahimi, and G. Panahi, Evaluation of Antioxidant Potential and Free Radical Scavenging Activity of Methanol Extract from Scrophularia striata. Acta Biochimica Iranica, 2023. 1(2): p. 71-77.
8. Falcone, C., E. Emanuele, A. D’Angelo, M.P. Buzzi, C. Belvito, M. Cuccia, et al., Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arteriosclerosis, thrombosis, and vascular biology, 2005. 25(5): p. 1032-1037.
9. Fadaei R, Adipokines as a link between adipose tissue with inflammation and insulin resistance in cardiometabolic diseases. Acta Biochimica Iranica, 2023. 1(3): p. 112-118.
10. Cesari, M., M. Pahor, and R.A. Incalzi, Plasminogen activator inhibitor‐1 (PAI‐1): a key factor linking fibrinolysis and age‐related subclinical and clinical conditions. Cardiovascular therapeutics, 2010. 28(5): p. e72-e91.
11. Sillen, M. and P.J. Declerck, Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition. Frontiers in Cardiovascular Medicine, 2020. 7: p. 622473.
12. Zhou, X., M.L. Hendrickx, G. Hassanzadeh-Ghassabeh, S. Muyldermans, and P.J. Declerck, Generation and in vitro characterisation of inhibitory nanobodies towards plasminogen activator inhibitor 1. Thrombosis and haemostasis, 2016. 116(12): p. 1032-1040.
13. Brogren, H., C. Sihlbom, K. Wallmark, M. Lönn, J. Deinum, L. Karlsson, et al., Heterogeneous glycosylation patterns of human PAI-1 may reveal its cellular origin. Thrombosis research, 2008. 122(2): p. 271-281.
14. Van De Craen, B., I. Scroyen, C. Vranckx, G. Compernolle, H.R. Lijnen, P.J. Declerck, et al., Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1. Thrombosis research, 2012. 129(4): p. e126-e133.
15. Gils, A., K.E. Pedersen, P. Skottrup, A. Christensen, D. Naessens, J. Deinum, et al., Biochemical importance of glycosylation of plasminogen activator inhibitor-1. Thrombosis and haemostasis, 2003. 90(08): p. 206-217.
16. Stadler, K., V. Jenei, A. Somogyi, and J. Jakus, Beneficial effects of aminoguanidine on the cardiovascular system of diabetic rats. Diabetes/metabolism research and reviews, 2005. 21(2): p. 189-196.
17. Oak, J.-H., J.-Y. Youn, and H. Cai, Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice. Cardiovascular Diabetology, 2009. 8(1): p. 1-7.
18. Furman, B.L., Streptozotocin‐induced diabetic models in mice and rats. Current protocols in pharmacology, 2015. 70(1): p. 5.47. 1-5.47. 20.
19. Khalid, M., G. Petroianu, and A. Adem, Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules, 2022. 12(4).
20. Vistoli, G., D. De Maddis, A. Cipak, N. Zarkovic, M. Carini, and G. Aldini, Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res, 2013. 47 Suppl 1: p. 3-27.
21. Magdaleno, F., C.C. Blajszczak, C.L. Charles-Niño, A.M. Guadrón-Llanos, A.O. Vázquez-Álvarez, A.G. Miranda-Díaz, et al., Aminoguanidine reduces diabetes-associated cardiac fibrosis. Exp Ther Med, 2019. 18(4): p. 3125-3138.
22. Nagai, R., D.B. Murray, T.O. Metz, and J.W. Baynes, Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes, 2012. 61(3): p. 549-559.
23. A Shamsaldeen, Y., L. S Mackenzie, L. A Lione, and C. D Benham, Methylglyoxal, a metabolite increased in diabetes is associated with insulin resistance, vascular dysfunction and neuropathies. Current drug metabolism, 2016. 17(4): p. 359-367.
24. Jagdale, A.D., L.N. Bavkar, T.A. More, M.M. Joglekar, and A.U. Arvindekar, Strong inhibition of the polyol pathway diverts glucose flux to protein glycation leading to rapid establishment of secondary complications in diabetes mellitus. Journal of Diabetes and its Complications, 2016. 30(3): p. 398-405.
25. Rai, A.K., N. Jaiswal, C.K. Maurya, A. Sharma, I. Ahmad, S. Ahmad, et al., Fructose-induced AGEs-RAGE signaling in skeletal muscle contributes to impairment of glucose homeostasis. The Journal of Nutritional Biochemistry, 2019. 71: p. 35-44.
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Issue | Vol 1 No 4 (2023) | |
Section | Original Articles | |
DOI | https://doi.org/10.18502/abi.v1i4.14720 | |
Keywords | ||
Diabetes Amonoguanidine Plasminogen activator inhibitor-1 |
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