Myrtus communis L. Extract Ameliorates High Fat Diet Induced Kidney and Bladder Damage by Inhibiting Oxidative Stress and Inflammation

Abstract

Objective: Obesity is associated with many diseases, including urinary system disorders such as chronic kidney disease and overactive bladder syndrome. Myrtus communis L. (MC) extract has been reported to have antioxidant and anti-inflammatory effects. The aim of this study was to investigate the protective effects of MC extract on high-fat diet (HFD)-induced kidney and bladder damage. Materials and Methods: Wistar albino male rats were divided into three experimental groups: control, HFD and HFD+MC. Experimental groups were fed a standard diet (control group) or HFD (HFD and HFD+MC groups) for 16 weeks. MC extract (100 mg/kg) was administered to the HFD+MC group orally during the last 4 weeks (5 days/week) of the experiment. Highdensity lipoprotein, total cholesterol, triglyceride and leptin levels were measured in blood serum. Tissue malondialdehyde (MDA), glutathione (GSH), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and myeloperoxidase (MPO) levels were evaluated biochemically. Kidney and bladder morphology, NADPH oxidase-2 (NOX-2) and nuclear factor-kappa B (NF-ҡB)-positive and apoptotic cells were evaluated histologically. Results: Lipid profiles altered and leptin levels increased in blood serum. MDA, 8-OHdG and MPO levels increased and GSH level decreased in kidney and bladder in the HFD group. Moreover, degenerated kidney and bladder morphology, increased NOX-2 and NF-ҡB-positive and apoptotic cells were observed in this group. All of these biochemical and histological parameters were ameliorated in the HFD+MC group. Conclusion: HFD-induced obesity causes kidney and bladder damage by oxidative and inflammatory processes. MC extract may reduce oxidative stress and inflammation and play a protective role in obesity-related kidney and bladder damage.

Keywords

• High fat diet
• Myrtus communis L. extract
• kidney
• bladder
• oxidative stress
• inflammation

Supporting Institution

None

Thanks

The authors would like to thank Dr. Gizem Emre for her help in identification of the plant material.

References

1. 1. Stein CJ, Colditz GA. The epidemic of obesity. J Clin Endocrinol Metab 2004; 89(6): 2522-5. google scholar
2. 2. World Health Organization. Obesity and overweight. 2021 June 9 (cited 2022 March 12). Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and- overweight google scholar
3. 3. Ding S, Fan Y, Zhao N, Yang H, Ye X, He D, et al. High fat aggravates glucose homeostasis by chronic exposure to bisphenol A. J Endo-crinol 2014; 221: 167-79. google scholar
4. 4. Ejerblad E, Fored CM, Lindblad P, Fryzek J, McLaughlin JK, et al. Obesity and risk for chronic renal failure. J Am Soc Nephrol 2006; 17(6): 1695-702. google scholar
5. 5. Lin Y, Wang Y, Wu Q, Jin H, Ma G, Liu H, et al. Association between obesity and bladder cancer recurrence: A meta-analysis. Clin Chim Acta 2018; 480: 41-6. google scholar
6. 6. Manna P, Jain SK. Obesity, oxidative stress, adipose tissue dysfunc-tion, and the associated health risks: causes and therapeutic strat-egies. Metab Syndr Relat Disord 2015; 13(10): 423-44. google scholar
7. 7. Kovesdy CP, Furth S, Zoccali C; World Kidney Day Steering Com-mittee. Obesity and kidney disease: Hidden consequences of the epidemic. Physiol Int 2017; 104(1): 1-14. google scholar
8. 8. Hua W, Huang HZ, Tan LT, Wan JM, Gui HB, Zhao L, et al. CD36 me-diated fatty acid-induced podocyte apoptosis via oxidative stress. PLoS One 2015; 10(5): e0127507. google scholar

9. 9. Lakkis JI, Weir MR. Obesity and Kidney Disease. Prog Cardiovasc Dis 2018; 61(2): 157-67. google scholar
10. 10. Powers SA, Ryan TE, Pak ES, Fraser MO, McClung JM, Hannan JL. Chronic high-fat diet decreased detrusor mitochondrial respira-tion and increased nerve-mediated contractions. Neurourol Uro-dyn 2019; 38(6): 1524-32. google scholar
11. 11. Alhasson F, Seth RK, Sarkar S, Kimono DA, Albadrani MS, Dattaroy D, et al. High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pa-thology in nonalcoholic fatty liver disease. Redox Biol 2018; 17: 1-15. google scholar
12. 12. Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-0-mediated fibrotic responses. Redox Biol 2014; 2: 267-72. google scholar
13. 13. Yu J, Cui PJ, Zeng WL, Xie XL, Liang WJ, Lin GB, et al. Protective effectof selenium-polysaccharides from the mycelia of Coprinus comatus onalloxan-induced oxidative stress in mice, Food Chem 2009; 117:42-7. google scholar
14. 14. Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. Reg-ulatory mechanisms for adipose tissue M1 and M2 macrophages indiet-induced obese mice. Diabetes 2009; 58: 2574-82. google scholar
15. 15. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression oftumor necrosis factor-a: direct role in obesity-linked insulin re-sistance. Science 1993; 259: 87-91. google scholar
16. 16. Liu Y, Wang L, Luo M, Chen N, Deng X, He J, et al. Inhibition of PAI-1 attenuates perirenal fat inflammation and the associated nephropathy in high-fat diet-induced obese mice. Am JPhysiol En-docrinol Metab 2019; 316: 260-7. google scholar
17. 17. Lai J,Ge M, Shen S,Yang L,JinT,Cao D,etal.Activation ofNF^B-JM-JD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation. Bio-chim Biophys Acta Mol Basis Dis 2019; 1865(9): 2403-10. google scholar
18. 18. Meng R, Zhu DL, Bi Y, Yang DH, Wang YP. Apocynin improves insulin resistance through suppressing inflammation in high-fat diet-in-duced obese mice. Mediators Inflamm 2010; 2010: 858735. google scholar
19. 19. de Souza AC, Gallo CBM, Passos MCDF, Croccia C, Miranda GL, Sam-paio FJB, et al. Effect of a high-fat diet on the rat bladder wall and bioactive action of Brazil nut oil. Int Braz J Urol 2019; 45(1): 161-8. google scholar
20. 20. Aizawa N, Homma Y, Igawa Y. Influence of high fat diet feeding for 20 weeks on lower urinary tract function in mice. Low Urin Tract Symptoms 2013; 5: 101-8. google scholar
21. 21. Oberbach A, Schlichting N, Heinrich M, Kullnick Y, Lehmann S, Ad-ams V, et al. Hochfettdiat induziert molekulare und physiologische Dysfunktionen der Harnblase (High fat diet- induced molecular and physiological dysfunction of the urinary bladder). Urologe A 2014; 53(12): 1805-11. google scholar
22. 22. Gomez CS, Kanagarajah P, Gousse AE. Bladder dysfunction in pa-tients with diabetes. Curr Urol Rep 2011;12: 419-26. google scholar
23. 23. Mafra D, Borges NA, Lindholm B, Shiels PG, Evenepoel P, Stenvinkel P. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol 2021; 17(3): 153-71. google scholar
24. 24. Aleksic V, Knezevic P. Antimicrobial and antioxidative activity of ex-tracts and essential oils of Myrtus communis L. Microbiol Res 2014; 169(4): 240-54. google scholar
25. 25. Odeh D, Orsolic N, Berendika M, Dikic D, Drozdek SD, Balbino S, et al. Antioxidant and anti-atherogenic activities of essential oils from Myrtus communis L. and Laurus nobilis L. in Rat. Nutrients 2022; 14(7): 1465. google scholar
26. 26. Tuzlacı E. Türkiye’nin geleneksel ilaç bitkileri. İstanbul: İstanbul Tıp Kitabevi; 2016. google scholar
27. 27. Berendika M, Domjanic Drozdek S, Odeh D, Orsolic N, Dragicevic P, Sokolovic M, et al. Beneficial effects of laurel (Laurus nobilis L.) and myrtle (Myrtus communis L.) extract on rat health. Molecules 2022; 27(2): 581. google scholar
28. 28. Hennia A, Miguel M, Nemmiche S. Antioxidant activity of Myrtus Communis L. and Myrtus Nivellei Batt. & Trab. extracts: A brief re-view. Medicines (Basel) 2018; 5(3): 89. google scholar
29. 29. Rosa A, Deiana M, Casu V, Corona G, Appendino G, Bianchi F, et al. Antioxidant activity of oligomeric acylphloroglucinols from Myr-tus communis L. Free Radic Res 2003; 37(9): 1013-19. google scholar
30. 30. Rossi A, Di Paola R, Mazzon E, Genovese T, Caminiti R, Bramanti P, et al. Myrtucommulone from Myrtus communis exhibits potent an-ti-inflammatory effectiveness in vivo. J Pharmacol Exp Ther 2009; 329(1): 76-86. google scholar
31. 31. Aidi Wannes W, Mhamdi B, Sriti J, Ben Jemia M, Ouchikh O, Hamd-aoui G, et al. Antioxidant activities of the essential oils and metha-nol extracts from myrtle (Myrtus communis var. italica L.) leaf, stem and flower. Food Chem Toxicol 2010; 48(5): 1362-70. google scholar
32. 32. Arslan S, Ozcan O, Gurel-Gokmen B, Cevikelli-Yakut ZA, Saygı HI, Sen A, et al. Myrtle improves renovascular hypertension-induced oxidative damage in heart, kidney, and aortic tissue. Biologia 2022; 77: 1877-88. google scholar
33. 33. Sen A, Ozkan S, Recebova K, Cevik O, Ercan F, Demirci EK, et al. Ef-fects of Myrtus communis extract treatment in bile duct ligated rats. J Surg Res 2016; 205 (2): 359-67. google scholar
34. 34. Aykac A, Ozbeyli D, Uncu M, Ertaş B, Kılınc O, Şen A, et al. Evaluation of the protective effect of Myrtus communis in scopolamine-in-duced Alzheimer model through cholinergic receptors. Gene 2019; 689: 194-201. google scholar
35. 35. Sen A, Yuksel M, Bulut G, Bitis L, Ercan F, Ozyilmaz-Yay N, et al. Ther-apeutic potential of Myrtus communis subsp. Communis extract against acetic acid-induced colonic inflammation in rats. J Food Biochem 2017; 41 (1): e12297. google scholar
36. 36. Atici AE, Arabacı Tamer S, Levent HN, Peker Eyüboğlu İ, Ercan F, Ak-kiprik M, et al. Neuropeptide W attenuates oxidative multi-organ injury in rats induced with intra-abdominal sepsis. Inflammation 2022; 45(1): 279-96. google scholar
37. 37. Koca O, Gokce AM, Akyuz M, Ercan F, Yurdakul N, Karaman MI. A new problem in inflammatory bladder diseases: use of mobile phones! Int Braz J Urol 2014; 40(4): 520-5. google scholar
38. 38. Acikel Elmas M, Cakıcı SE, Dur IR, Kozluca I, Arınc M, Binbuga B, Bingol Ozakpınar O, Kolgazi M, Sener G, Ercan F. Protective effects of exercise on heart and aorta in high-fat diet- induced obese rats. Tissue Cell 2019; 57: 57-65. google scholar
39. 39. Fan EWC, Chen LJ, Cheng JT, Tong YC. Changes of urinary bladder contractility in high-fat diet-fed mice: the role of tumor necrosis factor-a.IntJUrol 2014;21(8):831-5. google scholar
40. 40. Kuru Yaşar R, Kuru D, Şen A, Şener G, Ercan F, Yarat A. Effects of Myr-tus communis L. extract and apocynin on lens oxidative damage and boron levels in rats with a high fat-diet. Turk J Ophthalmol 2021; 51(6): 344-50. google scholar
41. 41. Qiu S, Sun G, Zhang Y, Li X, Wang R. Involvement ofthe NF--kB sig-naling pathway in the renoprotective effects of isorhamnetin in a type 2 diabetic rat model. Biomed Rep 2016; 4(5): 628-34. google scholar
42. 42. Zhang L, Yang Z, Zhao Y, Yang X, Meng X, Liu J, et al. Renoprotec-tive effects of Gushen Jiedu capsule on diabetic nephropathy in rats. Sci Rep 2020; 10(1): 2040. google scholar
43. 43. Ahmed AH. Flavonoid content and antiobesity activity of leaves of Myrtus Communis. Asian J Chem 2013; 25(12): 6818-22. google scholar
44. 44. Susztak K, Ciccone E, McCue P, Sharma K, Böttinger EP. Multiple metabolic hits converge on CD36 as novel mediator of tubular ep-ithelial apoptosis in diabetic nephropathy. PLoS Med 2009; 2(2): e45. google scholar
45. 45. Tas S, Tas B, Bassalat N, Jaradat N. In-vivo, hypoglycemic, hypolipid-emic and oxidative stress inhibitory activities of Myrtus communis L. fruits hydroalcoholic extract in normoglycemic and streptozoto-cin-induced diabetic rats. Biomed Res 2018; 29 (13): 2727-34. google scholar
46. 46. Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its pe-ripheral actions and interactions. Int J Obes Relat Metab Disord 2002; 26(11): 1407-33. google scholar
47. 47. Kashiwagi E, Abe T, Kinoshita F, Ushijima M, Masaoka H, Shiota M, et al. The role of adipocytokines and their receptors in bladder can-cer: expression of adiponectin or leptin is an independent prog-nosticator. Am J Transl Res 2020; 12(6): 3033-45. google scholar
48. 48. Garaa-Arroyo FE, Gonzaga-Sanchez G, Tapia E, Munoz-Jimenez I, Manterola-Romero L, Osorio-Alonso H, et al. Osthol ameliorates kidney damage and metabolic syndrome induced by a high-fat/ high-sugar diet. Int J Mol Sci 2021; 22(5): 2431. google scholar
49. 49. Yamamoto T, Takabatake Y, Takahashi A, Kimura T, Namba T, Mat-suda J, et al. High-fat diet-induced lysosomal dysfunction and im-paired autophagic flux contribute to lipotoxicity in the kidney. J Am Soc Nephrol 2017; 28(5): 1534-51. google scholar
50. 50. Li N, Ding H, Li Z, Liu Y, Wang P. Effect of high-fat diet-induced obe-sity on the small-conductance Ca2+-activated K+ channel func-tion affecting the contractility of rat detrusor smooth muscle. Int Urol Nephrol 2019; 51(1): 61-72. google scholar
51. 51. Lee M, Zhao H, Liu X, Liu D, Chen J, Li Z, et al. Protective effect of hydroxysafflor yellow a on nephropathy by attenuating oxidative stress and inhibiting apoptosis in induced type 2 diabetes in rat. Oxid Med Cell Longev 2020; 11: 7805393. google scholar
52. 52. Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Cohen SM. Effects of co-administration of dietary sodium arsenite and an NA-DPH oxidase inhibitor on the rat bladder epithelium. Toxicology 2009; 261(1-2): 41-6. google scholar
53. 53. Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta 2004 Jan; 339(1-2): 1-9. google scholar
54. 54. Takagi S, Li J, Takagaki Y, Kitada M, Nitta K, Takasu T, et al. Ipragli-flozin improves mitochondrial abnormalities in renal tubules in-duced by a high-fat diet. J Diabetes Investig 2018; 9(5): 1025-32. google scholar
55. 55. Li L, Zhao Z, Xia J, Xin L, Chen Y, Yang S, et al. A long-term high-fat/high-sucrose diet promotes kidney lipid deposition and causes apoptosis and glomerular hypertrophy in Bama minipigs. PLoS One 2015; 10(11): e0142884. google scholar
56. 56. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-45. google scholar
57. 57. Brovkovych V, Gao XP, Ong E, Brovkovych S, Brennan ML, Su X, et al. Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice. Am J Physiol Lung Cell Mol Physiol 2008; 295(1): L96-103. google scholar
58. 58. Elgazar-Carmon V, Rudich A, Hadad N, Levy R. Neutrophils tran-siently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 2008; 49(9): 1894-903. google scholar
59. 59. Wiersma JJ, Meuwese MC, van Miert JN, Kastelein A, Tijssen JG, Piek JJ, et al. Diabetes mellitus type 2 is associated with higher lev-els of myeloperoxidase. Med Sci Monit 2008; 14(8): CR406-10. google scholar
60. 60. Zhang H, Sun SC. NF--kB in inflammation and renal diseases. Cell Biosci 2015; 5: 63. google scholar
61. 61. Chenxu G, Xianling D, Qin K, Linfeng H, Yan S, Mingxin X, et al. Fise-tin protects against high fat diet-induced nephropathy by inhibit-ing inflammation and oxidative stress via the blockage of iRhom2/ NF--kB signaling. Int Immunopharmacol 2021 Mar; 92:107353. google scholar
62. 62. Fodor J, Fabry P, Lojda Z. The effect of long-term administration of diet with high fat content on the number of mast cells in the rat mesentery. Virchows Arch Pathol Anat Physiol Klin Med 1960; 333: 582-6. google scholar
63. 63. Wang CC, Kuo HC. Urothelial dysfunction and chronic inflamma-tion in diabetic patients with overactive bladder. Low Urin Tract Symptoms 2017; 9(3): 151-6. google scholar
64. 64. Djamali A, Reese S, Hafez O, Vidyasagar A, Jacobson L, Swain W, et al. Nox2 is a mediator of chronic CsA nephrotoxicity. Am J Trans-plant 2012; 12(8): 1997-2007. google scholar