Protective Effect of Betulinic Acid Administration on Kidney Damage in Acetaminophen-Induced Nephrotoxicity Model

Authors

Eda Dokumacioglu, Department of Nutrition and Dietetics, Faculty of Healthy Sciences, Artvin Coruh University, Artvin 08000, TurkeyFollow
Hatice İskender, Department of Nutrition and Dietetics, Faculty of Healthy Sciences, Artvin Coruh University, Artvin 08000, TurkeyFollow
Armagan Hayirli, Department of Animal Nutrition and Nutritional Disorders, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25420, TurkeyFollow
Guler Yenice, Department of Animal Nutrition and Nutritional Disorders, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25420, TurkeyFollow
Kubra Asena Terim Kapakin, Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25420, TurkeyFollow
Ismail Bolat, Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25420, TurkeyFollow
Esra Manavoglu Kirman, Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, Erzurum 25420, TurkeyFollow

ORCID ID

Eda Dokumacioglu : 0000-0002-2223-1331

Hatice Iskender : 0000-0002-8063-4972

Armagan Hayirli : 0000-0002-4446-0848

Guler Yenice : 0000-0003-0819-8843

Kubra Asena Terim Kapakin : 0000-0002-1740-8657

Ismail Bolat : 0000-0003-1398-7046

Esra Manavoglu Kirman : 0000-0003-3877-7686

Abstract

Background: Acetaminophen (APAP) is the most widely used analgesic drug worldwide, but it may induce renal toxicity. Betulinic acid (BA) ameliorates the oxidative stress and inflammatory response to renal damage. The present study aimed to investigate the potential protective effects of BA treatment through an experimental kidney damage rat model administered with APAP.

Methods: Sprague–Dawley male rats were randomly divided into four groups: control, BA (25 mg/kg for 15 days), APAP (1 g/kg), and APAP + BA groups. BA was administered via oral gavage at a dose of 25 mg/kg for 15 days. APAP was dissolved in hot saline and administered on the last day to produce nephrotoxicity via a single oral gavage at a dose of 1 g/kg. Kidney tissue samples were analyzed for human cartilage glycoprotein 39 (YKL-40), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18), superoxide dismutase (SOD), and malondialdehyde (MDA). Data were subjected to one-way analysis of variance and the Wilcoxon rank-sum test

Results: Renal tissue YKL-40, KIM-1, IL-18, and MDA levels in the APAP group were significantly higher than those in the control group (p < 0.05). The BA treatment completely restored renal KIM-1, YKL-40, and MDA levels and partially restored renal IL-18 and SOD levels in the rats subjected to renal damage induction (p < 0.05). The intertubular regions of rats administered with APAP had degeneration, necrosis, and infiltration of inflammatory cells and were immunopositive for IL-1 beta and 8-hydroxy-2′-deoxyguanosine.

Conclusions: BA can be used in the prevention and replacement treatment of nephrotoxicity due to its inhibitory properties in multiple pathways and powerful antioxidant effects.

References

1. Brune K, Renner B, Tiegs G. Acetaminophen/ paracetamol: A history of errors, failures and false decisions. Eur J Pain. 2015;19:953–65.
2. Salama M, Elgamal M, Abdelaziz A, Ellithy M, Magdy D, Ali L, et al. Toll–like receptor 4 blocker as potential therapy for acetaminophen–induced organ failure in mice. Exp Ther Med. 2015;10(1):241–6.
3. Ghosh J, Das J, Manna P, Sil PC. Acetaminophen induced renal injury via oxidative stress and TNF–α production: therapeutic potential of arjunolic acid. Toxicology. 2010;268:8–18.
4. Alshahrani S, Ashafaq M, Hussain S, Mohammed M, Sultan M, Jali AM, et al. Renoprotective effects of cinnamon oil against APAP–Induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats. Saudi Pharm J. 2021;29:194–200.
5. Puthumana J, Thiessen-Philbrook H, Xu L, Coca SG, Garg AX, Himmelfarb J, et al. Biomarkers of inflammation and repair in kidney disease progression. J Clin Invest. 2021;131:e139927.
6. Persson F, Borg R. YKL–40 in dialysis patients: Another candidate in the quest for useful biomarkers in nephrology. Kidney Int. 2018;93:2–22.
7. Keskin GS, Helvacı Ö, Yayla Ç, Paşaoğlu Ö, Keskin Ç, Arınsoy T, et al. Relationship between plasma YKL–40 levels and endothelial dysfunction in chronic kidney disease. Turkish J Med Sci. 2019;49:139–46.
8. Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, et al. KIM–1–mediated phagocytosis reduces acute injury to the kidney. J Clin Invest. 2015;125:1620–36.
9. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule–1: A tissue and urinary biomarker for nephrotoxicant–induced renal injury. Am J Physiol Renal Physiol. 2004;286:F552–63.
10. Bonventre JV. Kidney injury molecule–1(KIM–1): A specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest Suppl. 2008;241:78–83.
11. Hegazy R, Salama A, Mansour D, Hassan A. Renoprotective Effect of Lactoferrin against chromium–induced acute kidney injury in rats: Involvement of IL–18 and IGF–1 Inhibition. PLoS One. 2016;11:e0151486.
12. Griffin BR, Faubel S, Edelstein CL. Biomarkers of drug–induced kidney toxicity. Ther Drug Monit. 2019;41:213–26.
13. Lou H, Li H, Zhang S, Lu H, Chen Q. A Review on preparation of betulinic acid and its biological activities. Molecules. 2021;26:5583.
14. Jiang W, Li X, Dong S, Zhou W. Betulinic acid in the treatment of tumour diseases: Application and research progress. Biomed Pharmacother. 2021;142:111990.
15. Ríos JL, Máñez S. New pharmacological opportunities for betulinic acid. Planta Med. 2018;84:8–19.
16. Nader MA, Baraka HN. Effect of betulinic acid on neutrophil recruitment and inflammatory mediator expression in lipopolysaccharide–induced lung inflammation in rats. Eur J Pharm Sci. 2012;46:106–13.
17. Dokumacioğlu E, Iskender H, Terim Kapakin KA, Yenice G, Mokthare B, Bolat İ, et al. Effect of betulinic acid administration on TLR-9/NF-κB /IL-18 levels in experimental liver injury. Turk J Med Sci. 2021;51:1544–53.
18. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34:497–500.
19. Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-–hidroxynonenal. Method Enzymol. 1990;186:407–21.
20. Terim–Kapakin KA, Gumus R, Imik H, Kapakin S, Saglam YS. 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;59:279–87.
21. 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;18:501–11.
22. Seok PR, Kim JH, Kwon HR, Heo JS, Choi JR, Shin JH. Protective effects of Gastrodia elata Blume on acetaminophen–induced liver and kidney toxicity in rats. Food Sci Biotechnol. 2018;27:1445–54.
23. Parlakpinar H, Örüm MH, Acet A. Free oxygen radicals in drug–induced nephrotoxicity. Fırat Univ Med J Health Sci. 2013;27:51–6.
24. Ogutmen MB. Acute renal failure. CVT Anaesth Inten Care Soc. 2011;17:25–33.
25. Naguib YM, Azmy RM, Samaka RM, Salem MF. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen–induced hepato–renal injury. BMC Complem Altern Med. 2014;14:494.
26. Das J, Ghosh J, Manna P, Sil PC. Taurine protects acetaminophen–induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology. 2010;269:24–34.
27. Hiragi S, Yamada H, Tsukamoto T, Yoshida K, Kondo N, Matsubara T, et al. Acetaminophen administration and the risk of acute kidney injury: A self–controlled case series study. Clin Epidemiol. 2018;10:265–76.
28. Coban FK, Ince S, Demirel HH, Islam I, Aytug H. Acetaminophen–induced nephrotoxicity: Suppression of apoptosis and endoplasmic reticulum stress using boric acid. Biol Trace Elem Res. 2023;201:242–9.
29. Kamiş N, Karabag CF. Investigation of caffeic acid phenethly ester effect on inflammation and oxidative stress in paracetamol induced hepatotoxicity. Atatürk Uni Vet J. 2019;14:290–8.
30. Jaeschke H, McGill MR, Williams CD, Ramachandran A. Current issues with acetaminophen hepatotoxicity–A clinically relevant model to test the efficacy of natural products. Life Sci. 2011;88:737–45.
31. Aydin S, Atukeren P, Cakatay U, Uzun H, Altuğ T. Gender-dependent oxidative variations in liver of aged rats. Biogerontology. 2010;11:335-46.
32. Costa NA, Gut AL, Azevedo PS, Tanni SE, Cunha NB, Magalhães ES, et al. Erythrocyte superoxide dismutase as a biomarker of septic acute kidney injury. Ann Intens Care. 2016;6:95–102.
33. Mortensen J, Shames B, Johnson CP, Nilakantan V. MnTMPyP, a superoxide dismutase/catalase mimetic, decreases inflammatory indices in ischemic acute kidney injury. Inflamm Res. 2011;60:299–307.
34. Zhou XR, Bai YY, Qian LB. Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function. Clin J Biochem Mol Biol. 2018;34:455.
35. Adeleke GE, Adaramoye OA. Betulinic acid abates N-nitrosodimethylamine-induced changes in lipid metabolism, oxidative stress, and inflammation in the liver and kidney of Wistar rats. J Biochem Mol Toxicol. 2021;35:e22901.
36. El–Sayed EM, Abd-Allah AR, Mansour AM, El-Arabey AA. Thymol and carvacrol prevent cisplatin-–induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol. 2015;29:165–72.
37. Ucar F, Taslipinar MY, Alp BF, Aydin I, Aydin FN, Agilli M, et al. The effects of N–acetylcysteine and ozone therapy on oxidative stress and inflammation in acetaminophen–induced nephrotoxicity model. Ren Fail. 2013;35:640–7.
38. Hirooka Y, Nozaki Y. Interleukin–18 in inflammatory kidney disease. Front Med (Lausanne). 2021;8:639103.
39. Shen Y, Jin X, Chen W, Gao C, Bian Q, Fan J, et al. Interleukin–22 ameliorated acetaminophen–induced kidney injury by inhibiting mitochondrial dysfunction and inflammatory responses. Appl Microbiol Biotechnol. 2020;104:5889–98.
40. Vaidya VS, Waikar SS, Ferguson MA, Collings FB, Sunderland K, Gioules C, et al. Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci. 2008;1:200–8.
41. Bonventre JV. Kidney injury molecule–1 (KIM–1): A urinary biomarker and much more. Nephrol Dial Transplant. 2009;24:3265–8.
42. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule–1 (KIM–1): A novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62:237–44.
43. Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, et al. Kidney injury molecule–1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010;28:478–85.
44. Edelstein CL, Faubel S. Biomarkers in acute kidney injury. In: Edelstein CL. Ed. Biomarkers of kidney disease, Academic Press, 2011, p. 177–232.
45. Kim BW, Kim BW, Kim HJ, Kim SH, Baik HJ, Kang MS, et al. 15–Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast–induced acute kidney injury. Ren Fail. 2021;43:168–79.
46. Li X, Wang X, Liu S, Wang J, Liu X, Zhu Y, et al. Betulinic acid attenuates T-2 toxin-induced cytotoxicity in porcine kidney cells by blocking oxidative stress and endoplasmic reticulum stress. Comp Biochem Physiol C Toxicol Pharmacol. 2021;249:109124.
47. Huang L, Zhu L, Ou Z, Ma C, Kong L, Huang Y, et al. Betulinic acid protects against renal damage by attenuation of oxidative stress and inflammation via Nrf2 signaling pathway in T-2 toxin-induced mice. Int Immunopharmacol. 2021;101:108210.
48. Bilim O, Takeishi Y, Kitahara T, Ishino M, Sasaki T, Suzuki S, et al. Serum YKL–40 predicts adverse clinical outcomes in patients with chronic heart failure. J Card Fail. 2010;16:873–9.
49. Okyay GU, Er RE, Tebudak MY, Paşaoğlu Ö, Inal S, Öneç K, et al. Novel inflammatory marker in dialysis patients: YKL–40. Ther Apher Dial. 2013;17:193–201.
50. Puthumana J, Hall IE, Reese PP, Schröppel B, Weng FL, Thiessen-Philbrook H, et al. YKL–40 associates with renal recovery in deceased donor kidney transplantation. J Am Soc Nephrol. 2017;28:661–70.
51. Recklies AD, White C, Ling H. The chitinase 3–like protein human cartilage glycoprotein 39 (hcgp39) stimulates proliferation of human connective–tissue cells and activates both extracellular signal regulated kinase and protein kinase B–mediated signalling pathways. Biochemi J. 2002;365:119–26.
52. Recklies AD, Ling H, White C, Bernier SM. Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes. J Biol Chem. 2005;280:41213–21.
53. Ozbek E. Induction of oxidative stress in kidney. Int J Nephrol. 2012;2012:465897.
54. Jafari Khataylou Y, Ahmadi Afshar S, Mirzakhani N. Betulinic acid reduces the complications of autoimmune diabetes on the body and kidney through effecting on inflammatory cytokines in C57BL/6 mice. Vet Res Forum. 2021;12:203–10.
55. Lingaraju MC, Pathak NN, Begum J, Balaganur V, Ramachandra HD, Bhat RA, et al. Betulinic acid attenuates renal oxidative stress and inflammation in experimental model of murine polymicrobial sepsis. Eur J Pharm Sci. 2015;70:12–21.
56. Wang S, Yang Z, Xiong F, Chen C, Chao X, Huang J, et al. Betulinic acid ameliorates experimental diabetic-induced renal inflammation and fibrosis via inhibiting the activation of NF-κB signaling pathway. Mol Cell Endocrinol. 2016;434:135–43.

Recommended Citation

Dokumacioglu E, İskender H, Hayirli A, Yenice G, Kapakin KA, Bolat I, et al. Protective Effect of Betulinic Acid Administration on Kidney Damage in Acetaminophen-Induced Nephrotoxicity Model. Makara J Health Res. 2023;27.

Creative Commons License

This work is licensed under a Creative Commons Attribution-Share Alike 3.0 License.