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Liraglutide Attenuates Gentamicin-Induced Nephrotoxicity in Rats by Reducing Oxidative Stress

Year 2024, Volume: 19 Issue: 2, 68 - 77, 29.06.2024
https://doi.org/10.33719/nju1447326

Abstract

Objective: Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe Gram-negative infections. As we know, treatment with liraglutide has been shown to reduce oxidative stress. Therefore, we evaluated the potential protective effect of liraglutide against GEN-induced nephrotoxicity in rats.
Material And Methods: Twenty-eight rats were randomly divided into four groups: control group (Group 1); rats intraperitoneally injected with GEN (100 mg/kg/day; Group 2); rats treated with GEN plus distilled water (Group 3); and rats treated with GEN plus liraglutide (0.6 mg/kg/day; Group 4). After 15 days, the rats were sacrificed, their kidneys taken, and blood analysis performed. Tubular necrosis, interstitial fibrosis, and inducible nitric oxide synthetase (iNOS) scores were determined histopathologically in a part of the kidneys; malondialdehyde (MDA), reduced glutathione (GSH), E-cadherin and transforming growth factor β1 (TGF-β1) levels were determined in another part of kidneys.
Results: The GSH levels in renal tissue of only GEN-treated rats were significantly lower than others, and the administration of liraglutide to rats significantly increased the level of GSH. The group that was given GEN plus liraglutide had significantly lower MDA, TGF - β1, and E - cadherin levels than that given GEN alone. The rats treated with GEN+liraglutide indicated less severe tubular necrosis and their glomeruli maintained a better morphology compared to the GEN group. iNOS expression was higher in the liraglutide administrated group than the group that applied only GEN.
Conclusion: Liraglutide exerts protective effects on GEN-induced kidney damage by reducing oxidative stress in rat model.

Ethical Statement

Ethics committee approval was obtained by applying to the Istanbul University Animal Experiments Local Ethics Committee before the experiment (Approval number: 06/06/2018-147577). The study protocol conformed to the ethical guidelines of the Helsinki Declaration.

Supporting Institution

The authors declared that this study has received no financial support.

References

  • 1. Otunctemur A, Ozbek E, Cekmen M, Cakir SS, Dursun M, Polat EC, et al. Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Renal Failure. 2013;35(3):403–10. https://doi.org/10.3109/0886022X.2012.761040
  • 2. Simmons CF, Bogusky RT, Humes HD. Inhibitory effects of gentamicin on renal mitochondrial oxidative phosphorylation. Journal of Pharmacology and Experimental Therapeutics. 1980;214(3):709–15.
  • 3. Hur E, Garip A, Camyar A, Ilgun S, Ozisik M, Tuna S, et al. The effects of vitamin D on gentamicin-induced acute kidney injury in experimental rat model. International Journal of Endocrinology. 2013;2013. https://doi.org/10.1155/2013/313528
  • 4. Banday AA, Farooq N, Priyamvada S, Yusufi ANK, Khan F. Time dependent effects of gentamicin on the enzymes of carbohydrate metabolism, brush border membrane and oxidative stress in rat kidney tissues. Life Sciences. 2008;82(9–10):450–9. https://doi.org/10.1016/j.lfs.2007.11.014
  • 5. Pedraza-Chaverrí J, Maldonado PD, Medina-Campos ON, Olivares-Corichi IM, Granados-Silvestre MDLÁ, Hernández-Pando R, et al. Garlic ameliorates gentamicin nephrotoxicity: Relation to antioxidant enzymes. Free Radical Biology and Medicine. 2000;29(7):602–11. https://doi.org/10.1016/s0891-5849(00)00354-3
  • 6. Cekmen M, Otunctemur A, Ozbek E, Cakir SS, Dursun M, Polat EC, et al. Pomegranate extract attenuates gentamicin-induced nephrotoxicity in rats by reducing oxidative stress. Renal Failure. 2013;35(2):268–74. https://doi.org/10.3109/0886022X.2012.743859
  • 7. Dursun M, Sahin S, Besiroglu H, Otunctemur A, Ozbek E, Cakir SS, et al. Protective effect of nebivolol on gentamicin-induced nephrotoxicity in rats. Bratislava Medical Journal. 2018;119(11):718–25. https://doi.org/10.4149/BLL_2018_128
  • 8. Balakumar P, Rohilla A, Thangathirupathi A. Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it? Vol. 62, Pharmacological Research. 2010. p. 179–86. https://doi.org/10.1016/j.phrs.2010.04.004
  • 9. Shiraki A, Oyama J ichi, Komoda H, Asaka M, Komatsu A, Sakuma M, et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012;221(2):375–82. https://doi.org/10.1016/j.atherosclerosis.2011.12.039
  • 10. Batchuluun B, Inoguchi T, Sonoda N, Sasaki S, Inoue T, Fujimura Y, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis. 2014;232(1):156–64. https://doi.org/10.1016/j.atherosclerosis.2013.10.025
  • 11. Okada K, Kotani K, Yagyu H, Ando A, Osuga J ichi, Ishibashi S. Effects of treatment with liraglutide on oxidative stress and cardiac natriuretic peptide levels in patients with type 2 diabetes mellitus. Vol. 47, Endocrine. 2014. p. 962–4.
  • 12. Parthsarathy V, Hölscher C. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. European Journal of Pharmacology. 2013;700(1–3):42–50. https://doi.org/10.1016/j.ejphar.2012.12.012
  • 13. Kinugasa F, Noto T, Matsuoka H, Urano Y, Sudo Y, Takakura S, et al. Prevention of renal interstitial fibrosis via histone deacetylase inhibition in rats with unilateral ureteral obstruction. Transplant Immunology. 2010;23(1–2):18–23. https://doi.org/10.1016/j.trim.2010.02.003
  • 14. Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E, et al. Benefical effects of lycopene against contrast medium-induced oxidative stress, inflammation, autophagy, and apoptosis in rat kidney. Human and Experimental Toxicology. 2015;34(5):487–96. https://doi.org/10.1177/0960327114542964
  • 15. Quiros Y, Vicente-Vicente L, Morales AI, López-Novoa JM, López-Hernández FJ. An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin. Toxicological Sciences. 2011;119(2):245–56. https://doi.org/10.1093/toxsci/kfq267
  • 16. Silan C, Uzun Ö, Çomunoǧlu NÜ, Gokçen S, Bedirhan S, Cengiz M. Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol. Biological and Pharmaceutical Bulletin. 2007;30(1):79–83. https://doi.org/10.1248/bpb.30.79
  • 17. Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S. Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. In: Annals of the New York Academy of Sciences. 2001. p. 200–15.
  • 18. Ross D. Glutathione, free radicals and chemotherapeutic agents. Mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacology and Therapeutics. 1988;37(2):231–49. https://doi.org/10.1016/0163-7258(88)90027-7
  • 19. Chamberlain CG, Mansfield KJ, Cerra A. Nitric oxide, a survival factor for lens epithelial cells. Molecular Vision. 2008;14:983–91.

Liraglutide Attenuates Gentamicin-Induced Nephrotoxicity in Rats by Reducing Oxidative Stress

Year 2024, Volume: 19 Issue: 2, 68 - 77, 29.06.2024
https://doi.org/10.33719/nju1447326

Abstract

Objective: Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe Gram-negative infections. As we know, treatment with liraglutide has been shown to reduce oxidative stress. Therefore, we evaluated the potential protective effect of liraglutide against GEN-induced nephrotoxicity in rats.
Material And Methods: Twenty-eight rats were randomly divided into four groups: control group (Group 1); rats intraperitoneally injected with GEN (100 mg/kg/day; Group 2); rats treated with GEN plus distilled water (Group 3); and rats treated with GEN plus liraglutide (0.6 mg/kg/day; Group 4). After 15 days, the rats were sacrificed, their kidneys taken, and blood analysis performed. Tubular necrosis, interstitial fibrosis, and inducible nitric oxide synthetase (iNOS) scores were determined histopathologically in a part of the kidneys; malondialdehyde (MDA), reduced glutathione (GSH), E-cadherin and transforming growth factor β1 (TGF-β1) levels were determined in another part of kidneys.
Results: The GSH levels in renal tissue of only GEN-treated rats were significantly lower than others, and the administration of liraglutide to rats significantly increased the level of GSH. The group that was given GEN plus liraglutide had significantly lower MDA, TGF - β1, and E - cadherin levels than that given GEN alone. The rats treated with GEN+liraglutide indicated less severe tubular necrosis and their glomeruli maintained a better morphology compared to the GEN group. iNOS expression was higher in the liraglutide administrated group than the group that applied only GEN.
Conclusion: Liraglutide exerts protective effects on GEN-induced kidney damage by reducing oxidative stress in rat model.

Ethical Statement

Ethics committee approval was obtained by applying to the Istanbul University Animal Experiments Local Ethics Committee before the experiment (Approval number: 06/06/2018-147577).

References

  • 1. Otunctemur A, Ozbek E, Cekmen M, Cakir SS, Dursun M, Polat EC, et al. Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Renal Failure. 2013;35(3):403–10. https://doi.org/10.3109/0886022X.2012.761040
  • 2. Simmons CF, Bogusky RT, Humes HD. Inhibitory effects of gentamicin on renal mitochondrial oxidative phosphorylation. Journal of Pharmacology and Experimental Therapeutics. 1980;214(3):709–15.
  • 3. Hur E, Garip A, Camyar A, Ilgun S, Ozisik M, Tuna S, et al. The effects of vitamin D on gentamicin-induced acute kidney injury in experimental rat model. International Journal of Endocrinology. 2013;2013. https://doi.org/10.1155/2013/313528
  • 4. Banday AA, Farooq N, Priyamvada S, Yusufi ANK, Khan F. Time dependent effects of gentamicin on the enzymes of carbohydrate metabolism, brush border membrane and oxidative stress in rat kidney tissues. Life Sciences. 2008;82(9–10):450–9. https://doi.org/10.1016/j.lfs.2007.11.014
  • 5. Pedraza-Chaverrí J, Maldonado PD, Medina-Campos ON, Olivares-Corichi IM, Granados-Silvestre MDLÁ, Hernández-Pando R, et al. Garlic ameliorates gentamicin nephrotoxicity: Relation to antioxidant enzymes. Free Radical Biology and Medicine. 2000;29(7):602–11. https://doi.org/10.1016/s0891-5849(00)00354-3
  • 6. Cekmen M, Otunctemur A, Ozbek E, Cakir SS, Dursun M, Polat EC, et al. Pomegranate extract attenuates gentamicin-induced nephrotoxicity in rats by reducing oxidative stress. Renal Failure. 2013;35(2):268–74. https://doi.org/10.3109/0886022X.2012.743859
  • 7. Dursun M, Sahin S, Besiroglu H, Otunctemur A, Ozbek E, Cakir SS, et al. Protective effect of nebivolol on gentamicin-induced nephrotoxicity in rats. Bratislava Medical Journal. 2018;119(11):718–25. https://doi.org/10.4149/BLL_2018_128
  • 8. Balakumar P, Rohilla A, Thangathirupathi A. Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it? Vol. 62, Pharmacological Research. 2010. p. 179–86. https://doi.org/10.1016/j.phrs.2010.04.004
  • 9. Shiraki A, Oyama J ichi, Komoda H, Asaka M, Komatsu A, Sakuma M, et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis. 2012;221(2):375–82. https://doi.org/10.1016/j.atherosclerosis.2011.12.039
  • 10. Batchuluun B, Inoguchi T, Sonoda N, Sasaki S, Inoue T, Fujimura Y, et al. Metformin and liraglutide ameliorate high glucose-induced oxidative stress via inhibition of PKC-NAD(P)H oxidase pathway in human aortic endothelial cells. Atherosclerosis. 2014;232(1):156–64. https://doi.org/10.1016/j.atherosclerosis.2013.10.025
  • 11. Okada K, Kotani K, Yagyu H, Ando A, Osuga J ichi, Ishibashi S. Effects of treatment with liraglutide on oxidative stress and cardiac natriuretic peptide levels in patients with type 2 diabetes mellitus. Vol. 47, Endocrine. 2014. p. 962–4.
  • 12. Parthsarathy V, Hölscher C. The type 2 diabetes drug liraglutide reduces chronic inflammation induced by irradiation in the mouse brain. European Journal of Pharmacology. 2013;700(1–3):42–50. https://doi.org/10.1016/j.ejphar.2012.12.012
  • 13. Kinugasa F, Noto T, Matsuoka H, Urano Y, Sudo Y, Takakura S, et al. Prevention of renal interstitial fibrosis via histone deacetylase inhibition in rats with unilateral ureteral obstruction. Transplant Immunology. 2010;23(1–2):18–23. https://doi.org/10.1016/j.trim.2010.02.003
  • 14. Buyuklu M, Kandemir FM, Ozkaraca M, Set T, Bakirci EM, Topal E, et al. Benefical effects of lycopene against contrast medium-induced oxidative stress, inflammation, autophagy, and apoptosis in rat kidney. Human and Experimental Toxicology. 2015;34(5):487–96. https://doi.org/10.1177/0960327114542964
  • 15. Quiros Y, Vicente-Vicente L, Morales AI, López-Novoa JM, López-Hernández FJ. An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin. Toxicological Sciences. 2011;119(2):245–56. https://doi.org/10.1093/toxsci/kfq267
  • 16. Silan C, Uzun Ö, Çomunoǧlu NÜ, Gokçen S, Bedirhan S, Cengiz M. Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol. Biological and Pharmaceutical Bulletin. 2007;30(1):79–83. https://doi.org/10.1248/bpb.30.79
  • 17. Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S. Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. In: Annals of the New York Academy of Sciences. 2001. p. 200–15.
  • 18. Ross D. Glutathione, free radicals and chemotherapeutic agents. Mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacology and Therapeutics. 1988;37(2):231–49. https://doi.org/10.1016/0163-7258(88)90027-7
  • 19. Chamberlain CG, Mansfield KJ, Cerra A. Nitric oxide, a survival factor for lens epithelial cells. Molecular Vision. 2008;14:983–91.
There are 19 citations in total.

Details

Primary Language English
Subjects Urology
Journal Section Research Article
Authors

Recep Burak Degirmentepe

Muammer Bozkurt

Osman Can

Mustafa Erkoc This is me 0000-0003-0679-2873

Hazal Ozturk Gurgen This is me

Funda Yildirim This is me 0000-0003-0232-2081

Fatih Hunc This is me

Fatma Ceyla Eraldemir This is me

Alper Ötünçtemur 0000-0002-0553-3012

Publication Date June 29, 2024
Submission Date March 6, 2024
Acceptance Date June 25, 2024
Published in Issue Year 2024 Volume: 19 Issue: 2

Cite

Vancouver Degirmentepe RB, Bozkurt M, Can O, Erkoc M, Ozturk Gurgen H, Yildirim F, Hunc F, Eraldemir FC, Ötünçtemur A. Liraglutide Attenuates Gentamicin-Induced Nephrotoxicity in Rats by Reducing Oxidative Stress. New J Urol. 2024;19(2):68-77.