The protective impact of glutamine on anti-tuberculosis drug-induced nephrotoxicity in Wistar rats

Abstract

This study assessed the protective effect of glutamine (GTN) against rifampicin/isoniazid/pyrazinamide/ethambutol (RIPE)-induced nephrotoxicity in rats. Thirty adult Wistar rats (200±20 g) of both sexes were grouped into 6 of 5 rats/group. The rats were treated daily for 30 days as follows: Group 1 (Vehicle control [normal saline 0.2mL]), group 2 (GTN 200 mg/kg), group 3 (RIPE 150, 75, 400 and 275 mg/kg in vehicle), group 4 (GTN 50 mg/kg +RIPE), group 5 (GTN 100 mg/kg +RIPE) and group 6 (GTN 200 mg/kg +RIPE). After treatment, blood samples were obtained and assessed for serum renal biomarkers. Kidneys were harvested, weighed and assessed for oxidative stress markers and histology. RIPE significantly (p<0.01) decreased body weight and significantly (p<0.01) increased kidney weight when compared to the control. Serum urea, creatinine, uric acid levels and kidney malondialdehyde levels were significantly (p<0.001) increased in RIPE-treated rats when compared to the control. Serum total protein, albumin, kidney glutathione, catalase, superoxide dismutase and glutathione peroxidase levels were significantly decreased (p<0.001) in RIPE-treated rats when compared to the control. RIPE caused tubular necrosis and collapsed glomeruli in the kidneys of rats. However, body and liver weights were significantly restored in GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05 and p<0.01, respectively when compared to RIPE. Serum and kidney oxidative stress markers were restored in GTN 50 mg/kg +RIPE, GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05, p<0.01 and p<0.001 respectively, when compared to RIPE. GTN restored kidney histology. GTN protects against RIPE-induced nephrotoxicity in a dose-related fashion.

Keywords

• Antituberculosis drug
• kidney
• toxicity
• glutamine
• prevention
• rat

References

1. References 1. Naidoo S, Meyers AM Drugs and the kidney S Afr Med J 2015;105(4):322
2. 2. Awdishu, L., Mehta, R.L. The 6R’s of drug induced nephrotoxicity. BMC Nephrol 2017; 18, 124, 1-12
3. 3. Sahu N, Mishra G, Chandra HK, Nirala SK, Bhadauria M. Naringenin mitigates antituberculosis drugs induced hepatic and renal injury in rats. J Tradit Complement Med.2019; 10(1):26-35.
4. 4. De Vriese AS, Robbrecht DL, Vanholder RC, Vogelaers DP, Lameir NH. Rifampicin associated acute renal failure: pathophysiologic, immunologic and clinical. Am J Kidney Dis1999; 31:108-15
5. 5. Trainin EB, Turin RD. Gomez-Leon G. Acute renal insufficiency complicating isoniazid therapy. Int J Pediatric Nephrol. 1981; 14(1):53–54.
6. 6. Kwon SH, Kim JH, Yang JO, Lee EY, Hong SY. Ethambutol-induced acute renal failure. Nephrol Dial Transpl. Eur Renal Assoc.2004; 14(5):1335-1336
7. 7. Soffer O, Nassar VH, Campbell WG Jr, Bourke E. Light chain cast nephropathy and acute renal failure associated with rifampin therapy. Renal disease akin to myeloma kidney. Am J Med. 1987; 14(5):1052–1
8. 8. Sahu N, Mishra G, Chandra HK, Nirala SK, Bhadauria M. Naringenin mitigates antituberculosis drugs induced hepatic and renal injury in rats, J of Trad and Comp Med 200; 10 (1) 26-35,

9. 9. Covic A, Goldsmith DJ, Segall L, Stoicescu C, Lungu S, Volovat C, Covic M. Rifampicin-induced acute renal failure: a series of 60 patients. Nephrol Dial Transpl: Eur Renal Assoc. 1998;14(4):924–929
10. 10. Schubert C, Bates WD, Moosa MR. Acute tubulointerstitial nephritis related to antituberculous drug therapy. Clin Nephrol. 2010; 14(6):413–419.
11. 11. Melis GC, terWengel N, Boelens PG, van Leeuwen PA. Glutamine: recent developments in research on the clinical significance of glutamine. Curr Opin Clin Nutr Metab Care. 2004; 7:59–70.
12. 12. Novak F, Heyland DK, Avenell A. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med, 2002; 30:2022–9.
13. 13. Wischmeyer PE, Jayakar D, Williams U. Single dose of glutamine enhances myocardial tissue metabolism, glutathione content, and improves myocardial function after ischemia- reperfusion injury. J Parenter Enteral Nutr 2003; 27:396–403.
14. 14. Anders MW. Glutathione-dependent bioactivation of xenobiotics: implications for mutagenicity and carcinogenicity. Princess Takamatsu Symp. 199; 21:89–99.
15. 15. Dekant W, Vamvakas S. Glutathione-dependent bioactivation of xenobiotics. Xenobiotica. 1993; 23; 873-887
16. 16. Sadar S, Kaspate D, Vyawahare N. Protective effect of L-glutamine against diabetes- induced nephropathy in experimental animal: Role of KIM-1, NGAL, TGF-b1, and collagen-1Renal Failure, 2016; 38,. 9, 1483–1495
17. 17. Abraham P, Isaac B. The effects of oral glutamine on cyclophosphamide-induced nephrotoxicity in rats Premila. Human and Exp Toxicol, 2010, 30(7) 616–623
18. 18. Kim H, Park D, Kim JH, Jeong EY, Jung MH, Kim T, et al. Glutamine protects against cisplatin-induced nephrotoxicity by decreasing cisplatin accumulation, J Pharm Sci, 2015; 127 ( 1) 117-126.
19. 19. Mora LO, Antunes LMG, Francescato HDC, and Bianchi Mde L. The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats. Pharmacol Res 2003; 47: 517–522.
20. 20. Naserzadeh R, Jafaripour L, Eslamifar Z, Alizamani E, Nouryazdan, Ahmadvand H. The Effect of Receiving L-Glutamine on the Reduction of Renal Tissue Damages and Renal Function Recovery Following Gentamicin-Induced Nephrotoxicity in Rats. J Babol Univ Med Sci. 2021; 23: 267-74
21. 21. Buege JA, Aust SD. Microsomal lipid peroxidation. Meth Enzymol. 1978; 52: 302-310.
22. 22. Sun M, Zigman S. AnImproved Spectrophotometer Assay of Superoxide Dismutase Based On Epinephrine, Antioxidation. Analy Biochem 1978; 90: 81-89
23. 23. Sedlak, J, Lindsay RH. Estimation of total, protein-bound and non-protein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968; 25: 192-205 . 24. Rotruck JT, Rope AL, Ganther HF, Swason AB. Selenium: biochemical role as a component of glutathione peroxidase. Sci. 1973; 179: 588–590
24. 25. Aebi H Catalase in vitro. In Method in Enzymology, Colowick SP and Kaplane NO, Eds.,New York, NY, USA: Academic Press, 1984
25. 26. Prince SE, Martin SJ, Lavinya BU, Selvanathan K, Geetha A. Anti-tuberculosis drug-induced oxidative stress in kidneys: Role of brahmi as an antioxidant supplement. 2019; 15(62).12-16 27. Adikwu E, Biradee I, Ogungbaike TO. Therapeutic benefit of resveratrol on 5- fluorouracil-induced nephrotoxicity in rats. J Biomed Res, 2009; 6 (2) 11-16
26. 28. Adikwu E,Ebinyo NC, Jumbo P. Isoniazid/rifampicin-induced nephrotoxicity in rats: Protective Potential of selenium. J Integ Nephrol and Androl, 2020; 7: 34-40.
27. 29. Martin SJ, Sabina EP. Amelioration of antituberculosis drug induced oxidative stress in kidneys by Spirulina fusiformis in a rat model, Renal Failure, 2016. 38:7, 1115-1121,
28. 30. Sun Y. Free radicals, antioxidant enzymes, and carcinogenesis. Free Rad Biol & Med, 1990; 8, 583-599.
29. 31. Sharma R, Battu P, Singla M, Goyal N, Sharma VL. Expression profile of markers of oxidative stress, injury and apoptosis in anti-tuberculosis drugs induced nephrotoxicity. Nephrol (Carlton). 2019; 24(7):689-695.
30. 32. Hogg N. Free radicals in disease. Semin Reprod Endocrinol 1998; 16. (04), 241-248,
31. 33. Hu H, Chen L, Dai S, Li J, Bai X. Effect of Glutamine on Antioxidant Capacity and Lipid Peroxidation in the Breast Muscle of Heat-stressed Broilers via Antioxidant Genes and HSP70 Pathway. Animals (Basel). 2020; 10(3):404.
32. 34. Li H-T, Feng L, Jiang W-D, Liu Y, Jiang J, Li S-H. Oxidative stress parameters and anti- apoptotic response to hydroxyl radicals in fish erythrocytes: protective effects of glutamine, alanine, citrulline and proline. Aquat Toxicol. 2013; 126:169-79.
33. 35. Nam TG. Lipid peroxidation and its toxicological implications. Toxicol Res. (2011);27(1):1-6. 36. Adikwu E, Ebinyo NC, Benalayefa O. Protective effect of lycopene against tamoxifen-induced hepatotoxicity in albino rats. Biomed and Biotech Res J 2020;4:69-75.
34. 37. Hussein OE, Germoush MO, Mahmoud AM. RutagraveolensProtects Against Isoniazid/Rifampicin-Induced Nephrotoxicity through Modulation of Oxidative Stress and Inflammation. Glob J Biotechnol Biomater Sci 2016; 1(1): 017-022.
35. 38. CrissmanJW, Goodman DG, Hildebrandt PK, Maronpot RR, Prater DA, 5 Riley JH. Best Practices Guideline: Toxicol Pathol, 2004; 32:126–131.