Effects of oleanolic acid administration on renal NF-κB/IL-18/IL-6 and YKL-40/KIM-1 pathways in experimental diabetic rats

Document Type : Original Article

Authors

1 Artvin Coruh University, Faculty of Health Sciences, Department of Nutrition and Dietetics, Artvin 08000, Turkey

2 Department of Animal Nutrition and Nutritional Disorders, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25240, Turkey

3 Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25240, Turkey

Abstract

Objective(s): Neuropathy, retinopathy, and nephropathy, known as the triopathy of diabetes, are the consequences of microvascular complications of diabetes. The present study aimed to investigate the potential protective effects of oleanolic acid (OA) administration against diabetic nephropathy considering biochemical and histopathological parameters.
Materials and Methods: The rats with fasting blood glucose levels of 200 mg/dl and above were considered diabetic after induction of diabetes via injecting STZ. The other half of the rats were not injected with STZ (healthy rats). Both healthy and diabetic rats were then divided randomly into two subgroups to be administered with either OA (5 mg/kg) with 1 ml tap water by oral gavage or 1 ml tap water in the same route for 21 days. Serum urea-N, Ca, P, and Mg as well as renal tissue MDA, SOD, NF-κB, IL-6, IL-18, AMPK, YKL-40, and KIM-1 levels were measured.
Results: OA administration partially decreased levels of serum urea-N and P, as well as levels of renal tissue MDA and inflammation markers (NF-κB, IL-6, IL-18, YKL-40, and KIM-1) in the diabetic rats. It also partially increased serum Ca and renal tissue AMPK levels in diabetic rats. These positive effects were also seen in renal tissue histopathology.
Conclusion: OA treatment partially alleviated renal damage inflammatory and oxidative profiles in diabetic rats.

Keywords

Main Subjects

References

1. Petersmann A, Müller-Wieland D, Müller UA, Landgraf R, Nauck M, Freckmann G, et al. Definition, classification and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes 2019; 127: 1-7.
2. Karagecili H, İzol E, Kirecci E, Gulcin İ. Determination of antioxidant, anti-alzheimer, antidiabetic, antiglaucoma and antimicrobial effects of Zivzik Pomegranate (Punica granatum)-A chemical profiling by LC-MS/MS. Life (Basel) 2023; 9;13:735-761.
3. Atmaca U, Saglamtas R, Sert Y, Çelik M, Gülçin İ. Metal-free synthesis, enzyme ınhibition properties and molecular docking of novel ısoindolinones via ıntramolecular cyclization. ChemistrySelect 2023;8:e20220457.
4. Karagecili H, Yılmaz MA, Ertürk A, Kızıltaş H, Güven L, Alwasel SH, et al. Comprehensive metabolite profiling of Berdav propolis using LC-MS/MS: Determination of antioxidant, anticholinergic, antiglaucoma, and antidiabetic effects. Molecules 2023; 28: 1739-1758.
5. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther 2008; 88:1254-1264.
6. Tziomalos K, Athyros VG. Diabetic nephropathy: New risk factors and improvements in diagnosis. Rev Diabet Stud 2015; 12:110-118.
7. Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovas Ther 2012; 30: 49-59.
8. Mutlu M, Bingöl Z, Uç EM, Koksal E, Gören AC, Alwasel SH, et al. Comprehensive metabolite profiling of cinnamon (Cinnamomum zeylanicum) leaf oil using LC-HR/MS, GC/MS, and GC-FID: Determination of antiglaucoma, antioxidant, anticholinergic, and antidiabetic profiles. Life 2023; 13:136-153.
9. Kiziltas H, Gören AC, Alwasel S, Gulçin İ. Comprehensive metabolic profiling of Acantholimon caryophyllaceum using LC-HRMS and evaluation of antioxidant activities, enzyme inhibition properties and molecular docking studies. S Afr J Bot 2022; 151: 743-751.
10. Lopes AA. End-stage renal disease due to diabetes in racial/ethnic minorities and disadvantaged populations. Ethn Dis 2009; 19: 47-51.
11. Shah IM, Mackay SP, McKay GA. Therapeutic strategies in the treatment of diabetic nephropathy: A translational medicine approach. Curr Med Chem 2009; 16: 997-1016.
12. Kunnumakkara AB, Shabnam B, Girisa S, Harsha C, Banik K, Devi TB, et al. Inflammation, NF-κB, and chronic diseases: How are they linked? Crit Rev Immunol 2020; 40:1-39
13. Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Intl 2001; 59: 415-424
14. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 2001;107:1145-1152
15. Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19: 433-442
16. Wong CK, Ho AW, Tong PC, Yeung CY, Kong AP, Lun SW, et al. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. Clin Exp Immuno 2007; 49:123-131
17. Kismiroglu C, Cengiz S, Yaman M. Biochemistry of AMPK: Mechanisms of action and importance in the treatment of diabetes. European J Sci Tech 2020;18:162-170.
18. Luo W, Zhang L, Sheng L, Zhang Z, Yang Z. Increased levels of YKL-40 in patients with diabetes mellitus: A systematic review and meta-analysis. Diabetol Metab Syndr 2021; 13: 6-14.
19. Rathcke CN, Vestergaard H. YKL-40 a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. Inflammat Res 2006; 55: 221-227.
20. Khan FA, Fatima SS, Khan GM, Shahid S. Evaluation of kidney injury molecule-1 as a disease progression biomarker in diabetic nephropathy. Pak J Med Sci 2019; 35: 992-996.
21. Molitch ME, DeFronzo RA, Franz MJ, KeaneWF, Mogensen CE, Parving HH, et al. Nephropathy in diabetes. Diabetes Care 2004; 27:79-83.
22. Senol H, Çelik Turgut G, Şen A, Sağlamtaş R, Tuncay S, Gülçin İ, et al. Synthesis of nitrogen-containing oleanolic acid derivatives as carbonic anhydrase and acetylcholinesterase inhibitors. MCR 2003;32: 694-704.
23. Rodriguez-Rodriguez R. Oleanolic acid and related triterpenoids from olives on vascular function: Molecular mechanisms and therapeutic perspectives. Curr Med Chem 2015;22:1414-1425.
24. Pollier J, Goossens A. Oleanolic acid. Phytochemistry 2012; 77: 10-15.
25. Castellano JM, Ramos-Romero S, Perona JS. Oleanolic acid: Extraction characterization and biological activity. Nutrients 2022; 14: 623-641.
26. Ayeleso TB, Matumba MG, Mukwevho E. Oleanolic acid and its derivatives: Biological activities and therapeutic potential in chronic diseases. Molecule 2017; 22: 1915-1930.
27. Dokumacioglu E, Iskender H, Sen TM, Ince I, Dokumacioglu A, Kanbay Y, et al. The effects of hesperidin and quercetin on serum tumor necrosis factor-alpha and interleukin 6 levels in streptozotocin-induced diabetes model. Pharmacogn Mag 2018; 14: 167-173.
28. Iskender H, Dokumacioglu E, Terim-Kapakin KA, Yenice G, Mohtare B, Bolat I, et al. Effects of oleanolic acid on inflammation and metabolism in diabetic rats. Biotec Histochem 2022; 15: 1-8.
29. Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hidroxynonenal. Methods Enzymol 1990; 186: 407-421
30. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide Dismutase. Clin Chem 1988; 34: 497-500
31. Terim-Kapakin KA, Gumus R, Imik H, Kapakin S. Effects of ascorbic and α-lipoic acid on secretion of HSP-70 and apoptosis in liver and kidneys of broilers exposed to heat stress. Ankara Univ Vet J 2012; 59: 279-287.
32. Apaydin-Yildirim B, Kordali S, Terim-Kapakin KA, Yildirim F, Aktas Senocak E, Altun S. Effect of Helichrysum plicatum DC subsp plicatum ethanol extract on gentamicin induced nephrotoxicity in rats. J Zhejiang Univ Sci B 2017; 18:501-511.
33. Grossman LD, Roscoe R, Shack AR. Complementary and alternative medicine for diabetes. Can J Diabetes 2018; 42: 154-161.
34. Fioretto P, Bruseghin M, Barzon I, Arboit M, Vestra MD. Diabetic nephropathy: An update on renal structure. Int Congr Ser 2017; 1303: 51-59.
35. Ahn C, Kang JH, Jeung EB. Calcium homeostasis in diabetes mellitus. J Vet Sci 2017; 18: 261-266.
36. Barbagallo M, Dominguez LJ. Magnesium and type 2 diabetes. World J Diabetes 2015; 6: 1152-1157.
37. Carlioglu A, Akdeniz D, Alkan R, Uz E, Haltas H, Turgut F, Uysal S. The effect of zofenopril on pancreas kidney and liver of diabetic rats. Turk Neph Dial Transpl Turkish 2014; 23:118-124.
38. Masola B, Oguntibeju OO, Oyenihi AB. Centella asiatica ameliorates diabetes induced stress in rat tissues via influences on antioxidants and inflammatory cytokines. Biomed Pharmacother 2018; 101: 447-457.
39. Iskender H, Dokumacioglu E, Sen TM, Ince I, Kanbay Y, Saral S. The effect of hesperidin and quercetin on oxidative stress NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model. Bioméd & pharmacothér 2017;90:500-508.
40. Yalcin T, Rakicioglu N. Dietary Factors Type 2 Diabetes and Inflammation. Sakarya Med J 2018; 8: 686-694.
41. Xiao J, Li J, Cai L, Chakrabarti S, Li X. Cytokines and diabetes research. J Diabetes Res 2014; 2014: 920613-920615.
42. Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovas Ther 2012; 30: 49-59.
43. Baker RG, Hayden MS, Ghosh S. NF-κB inflammation and metabolic disease. Cell Metab 2011; 13:11-22.
44. Kang KS, Kim HY, Yamabe N, Nagai R, Yokozawa T. Protective effect of sun ginseng against diabetic renal damage. Biol Pharm Bull 2006; 29:1678-1684.
45. Norlin S, Ahlgren U, Edlund H. Nuclear factor-κB activity in β-cells is required for glucose- stimulated insulin secretion. Diabetes 2005; 54:125-132.
46. Dias AS, Porawski M, Alonso M, Marroni N, Collado PS, González-Gallego J. Quercetin decreases oxidative stress NF-κB activation and Inos overexpression in liver of streptozotocin-induced diabetic rats. J Nutr 2005; 135: 2299-2304.
47. Rivero A, Mora C, Muros M, García J, Herrera H, Navarro-González J. Pathogenic perspectives for the role of inflammation in diabetic nephropathy. Clin Sci 2009; 116: 479-492.
48. Araki S, Haneda M, Koya D, Sugimoto T, Isshiki K, Chin-Kanasaki M, et al. Predictive impact of elevated serum level of IL18 for early renal dysfunction in type 2 diabetes: An observational follow-up study. Diabetologia 2007; 50: 867-873.
49. Li M, Han Z, Bei W, Rong X, Guo J, Hu X. Oleanolic acid attenuates insulin resistance via NF-κB to regulate the IRS1-GLUT4 pathway in HepG2 cells. Evid Based Complement Alternat Med 2015; 2015: 643102-643110.
50. Wu Y, Viana M, Thirumangalathu S, Loeken MR. AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia 2012; 55: 245-254.
51. Mottillo EP, Desjardins EM, Fritzen AM, Zou VZ, Crane JD, Yabut JM, et al. FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis. Mol Metab 2017; 6:471-481.
52. Jiménez-Flores LM, López-Briones S, Macías-Cervantes MH, Ramírez-Emiliano J, Pérez Vázquez V. A PPARγ NF-κB and AMPK-dependent mechanism may be involved in the beneficial effects of curcumin in the diabetic db/db mice liver. Molecules 2014; 19: 289-8302.
53. Kim S, Lee MS, Jung S, Son HY, Park S, Kang B, et al. Ginger extract ameliorates obesity and inflammation via regulating microRNA-21/132 expression and AMPK activation in white adipose tissue. Nutrients 2018; 10:1567-1578.
54. Rathcke CN, Persson F, Tarnow L, Rossing P, Vestergaard H. YKL-40 a marker of inflammation and endothelial dysfunction is elevated in patients with type 1 diabetes and increases with levels of albuminuria. Diabetes Care 2009; 32: 323-328.
55. Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: The role of endothelial dysfunction. Clin Sci 2005; 109: 143-159.
56. Kapoula GV, Kontou PI, Bagos PG. Diagnostic Performance of biomarkers urinary KIM-1 and YKL-40 for early diabetic nephropathy in patients with type 2 diabetes: A systematic review and meta-analysis. Diagnostics 2020; 10: 1-14.
57. Parving HH. Diabetic nephropathy: Prevention and treatment. Kidney Int 2001; 60: 2041-2055.
58. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabetic nephropathy. Kidney Int 2001; 59: 702-709.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 10
October 2023
Pages 1188-1193

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