Reno-protective effect of agmatine in methotrexate-induced kidney injury in rats

Samar Shaban Hassan; Mohamed Mohamed Shebl; Marwa Nagy Emam; Abeer Abed Ahmed; Mohamed Mohamed Madi

doi:10.53730/ijhs.v9nS1.15697

Authors

Samar Shaban Hassan
samar.shaban@med.tanta.edu.eg
Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
Mohamed Mohamed Shebl Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
Marwa Nagy Emam Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
Abeer Abed Ahmed Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
Mohamed Mohamed Madi

Keywords:

Agmatine, Methotreaxate, Oxidative Stress, Rats, Renal Toxicity

Abstract

Background: L-arginine's endogenous metabolite agmatine (AGM) is recognized to have anti-inflammatory, anti-apoptotic, and antioxidant qualities. Investigating the dose-dependent renal-protective effect of AGM in rats with MTX-induced kidney damage was the goal of this study. Methods: In this experimental study, fifty male rats were divided into five groups (n = 10). Group I (control) received oral saline for 7 days and IP saline on day 7. Group II (MTX) received oral saline for 7 days and IP MTX (20 mg/kg) on day 7. Groups III–V received AGM orally at 10, 20, and 40 mg/kg/day for 7 days, followed by IP MTX (20 mg/kg) on day 7. Results: Intraperitoneal MTX (20 mg/kg) significantly increased renal somatic index, MDA, 8-OHdG, NO, TNF-α, IL-1, serum creatinine, BUN, and NF-κB, while it decreased GSH, SOD, HO-1 activity, Nrf2 expression, and creatinine clearance. AGM administration at various doses showed a protective renal effect against MTX-induced changes. Conclusions: Many disorders can be effectively treated with MTX. The toxicity of MTX, which includes nephrotoxicity with a mechanism involving inflammation and oxidative damage, frequently limits its therapeutic uses.

Downloads

Download data is not yet available.

Author Biography

Mohamed Mohamed Madi

Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

References

Abd El-Twab, S. M., Hussein, O. E., Hozayen, W. G., Bin-Jumah, M., & Mahmoud, A. M. (2019). Chicoric acid prevents methotrexate-induced kidney injury by suppressing NF-κB/NLRP3 inflammasome activation and up-regulating Nrf2/ARE/HO-1 signaling. Inflamm Res, 68(6), 511-523. doi:10.1007/s00011-019-01241-z DOI: https://doi.org/10.1007/s00011-019-01241-z

Aladaileh, S. H., Hussein, O. E., Abukhalil, M. H., Saghir, S. A. M., Bin-Jumah, M., Alfwuaires, M. A., . . . Mahmoud, A. M. (2019). Formononetin upregulates Nrf2/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants (Basel), 80(10), 17-25. doi:10.3390/antiox8100430 DOI: https://doi.org/10.3390/antiox8100430

Auguet, M., Viossat, I., Marin, J. G., & Chabrier, P. E. (1995). Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol, 69(3), 285-287. doi:10.1254/jjp.69.285 DOI: https://doi.org/10.1254/jjp.69.285

Barregard, L., Møller, P., Henriksen, T., Mistry, V., Koppen, G., Rossner, P., Jr., . . . Cooke, M. S. (2013). Human and methodological sources of variability in the measurement of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine. Antioxid Redox Signal, 18(18), 2377-2391. doi:10.1089/ars.2012.4714 DOI: https://doi.org/10.1089/ars.2012.4714

Bauer, J. H., Brooks, C. S., & Burch, R. N. (1982). Renal function studies in man with advanced renal insufficiency. Am J Kidney Dis, 2(1), 30-35. doi:10.1016/s0272-6386(82)80040-1 DOI: https://doi.org/10.1016/S0272-6386(82)80040-1

Berger, J., Leibowitz, M. D., Doebber, T. W., Elbrecht, A., Zhang, B., Zhou, G., . . . Moller, D. E. (1999). Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem, 274(10), 6718-6725. doi:10.1074/jbc.274.10.6718 DOI: https://doi.org/10.1074/jbc.274.10.6718

Bergin, D. H., Jing, Y., Williams, G., Mockett, B. G., Zhang, H., Abraham, W. C., & Liu, P. (2019). Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate. Sci Rep, 9(1), 126-150. doi:10.1038/s41598-019-49078-0 DOI: https://doi.org/10.1038/s41598-019-49078-0

Broeke, R. T., De Crom, R., Van Haperen, R., Verweij, V., Leusink-Muis, T., Van Ark, I., . . . Folkerts, G. (2006). Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice. Respir Res, 7(2), 1-13. DOI: https://doi.org/10.1186/1465-9921-7-58

Di Vita, G., Patti, R., Sparacello, M., Balistreri, C. R., Candore, G., & Caruso, C. (2008). Impact of different texture of polypropylene mesh on the inflammatory response. Int J Immunopathol Pharmacol, 21(1), 207-214. doi:10.1177/039463200802100123 DOI: https://doi.org/10.1177/039463200802100123

El-Sherbeeny, N. A., Nader, M. A., Attia, G. M., & Ateyya, H. (2016). Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways. Naunyn Schmiedebergs Arch Pharmacol, 389(12), 1341-1351. doi:10.1007/s00210-016-1284-9 DOI: https://doi.org/10.1007/s00210-016-1284-9

Elseady, W. S., Keshk, W. A., Elhanafy, H. A., & Abd Ellatif, R. (2023). Ameliorative potential of lactoferrin on methotrexate-induced nephrotoxicity in rat: a histological and immunohistochemical study. Egypt J Histol, 46(1), 49-64.

Gai, Z., Gui, T., Kullak-Ublick, G. A., Li, Y., & Visentin, M. (2020). The role of mitochondria in drug-induced kidney injury. Front Physiol, 11(5), 10-79. doi:10.3389/fphys.2020.01079 DOI: https://doi.org/10.3389/fphys.2020.01079

Han, N., Yu, L., Song, Z., Luo, L., & Wu, Y. (2015). Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition. Mol Med Rep, 12(1), 1098-1106. doi:10.3892/mmr.2015.3540 DOI: https://doi.org/10.3892/mmr.2015.3540

Heidari, R., Ahmadi, A., Mohammadi, H., Ommati, M. M., Azarpira, N., & Niknahad, H. (2018). Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance. Biomed Pharmacother, 107(12), 834-840. doi:10.1016/j.biopha.2018.08.050 DOI: https://doi.org/10.1016/j.biopha.2018.08.050

Howard, S. C., McCormick, J., Pui, C. H., Buddington, R. K., & Harvey, R. D. (2016). Preventing and managing toxicities of high-dose methotrexate. Oncologist, 21(12), 1471-1482. doi:10.1634/theoncologist.2015-0164 DOI: https://doi.org/10.1634/theoncologist.2015-0164

Kale, M., Nimje, N., Aglawe, M. M., Umekar, M., Taksande, B., & Kotagale, N. (2020). Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats. Brain Res, 1747(145), 147-160. doi:10.1016/j.brainres.2020.147045 DOI: https://doi.org/10.1016/j.brainres.2020.147045

Keates, S., Hitti, Y. S., Upton, M., & Kelly, C. P. (1997). Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterol, 113(4), 1099-1109. doi:10.1053/gast.1997.v113.pm9322504 DOI: https://doi.org/10.1053/gast.1997.v113.pm9322504

Kolli, V. K., Abraham, P., Isaac, B., & Selvakumar, D. (2009). Neutrophil infiltration and oxidative stress may play a critical role in methotrexate-induced renal damage. Chemotherapy, 55(2), 83-90. doi:10.1159/000192391 DOI: https://doi.org/10.1159/000192391

Li, B., Jiang, T., Liu, H., Miao, Z., Fang, D., Zheng, L., & Zhao, J. (2018). Andrographolide protects chondrocytes from oxidative stress injury by activation of the Keap1-Nrf2-Are signaling pathway. J Cell Physiol, 234(1), 561-571. doi:10.1002/jcp.26769 DOI: https://doi.org/10.1002/jcp.26769

Łuczak, A., Madej, M., Kasprzyk, A., & Doroszko, A. (2020). Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases. Oxid Med Cell Longev, 2020, 1417981. doi:10.1155/2020/1417981 DOI: https://doi.org/10.1155/2020/1417981

Miranda-Mosqueda, L., Ruiz-Oropeza, S., & Gomez-Acevedo, C. (2024). Neuroprotective effect of agmatine in ischemic vascular events. Med Res Arch, 12(1), 17-25. DOI: https://doi.org/10.18103/mra.v12i1.4928

Montgomery, H., & Dymock, J. (1961). Determination of nitrite in water. Royal soc chemistry thomas graham house, science park, milton rd, cambridge Cb4 0wf. J Med Lab Technol, 22(5), 111-118.

Moron, M. S., Depierre, J. W., & Mannervik, B. (1979). Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta, 582(1), 67-78. doi:10.1016/0304-4165(79)90289-7 DOI: https://doi.org/10.1016/0304-4165(79)90289-7

Nezu, M., & Suzuki, N. (2020). Roles of Nrf2 in protecting the kidney from oxidative damage. Int J Mol Sci, 21(8), 178-210. doi:10.3390/ijms21082951 DOI: https://doi.org/10.3390/ijms21082951

Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem, 95(2), 351-358. doi:10.1016/0003-2697(79)90738-3 DOI: https://doi.org/10.1016/0003-2697(79)90738-3

Ommati, M. M., Farshad, O., Mousavi, K., Taghavi, R., Farajvajari, S., Azarpira, N., . . . Heidari, R. (2020). Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice. PharmaNutrition, 13(4), 100-121. DOI: https://doi.org/10.1016/j.phanu.2020.100212

Ozawa, N., Goda, N., Makino, N., Yamaguchi, T., Yoshimura, Y., & Suematsu, M. (2002). Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress. J Clin Invest, 109(4), 457-467. doi:10.1172/jci13190 DOI: https://doi.org/10.1172/JCI0213190

Parasuraman, S., Ching, T. H., Leong, C. H., & Banik, U. (2019). Antidiabetic and antihyperlipidemic effects of a methanolic extract of Mimosa pudica (Fabaceae) in diabetic rats. Egypt. J Basic Appl Sci, 6(1), 137-148. DOI: https://doi.org/10.1080/2314808X.2019.1681660

Sah, S. K., Subramanian, R., & Ramesh, M. (2020). Methotrexate-induced organ toxicity in patients with rheumatoid arthritis: A review article. Drug Discov Today, 14(1), 178-190.

Salihoglu, Y. S., Elri, T., Gulle, K., Can, M., Aras, M., Ozacmak, H. S., & Cabuk, M. (2016). Evaluation of the protective effect of agmatine against cisplatin nephrotoxicity with 99mTc-DMSA renal scintigraphy and cystatin-C. Ren Fail, 38(9), 1496-1502. doi:10.1080/0886022x.2016.1227919 DOI: https://doi.org/10.1080/0886022X.2016.1227919

Sharawy, M. H., Abdelrahman, R. S., & El-Kashef, D. H. (2018). Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. Life Sci, 208, 79-86. doi:10.1016/j.lfs.2018.07.019 DOI: https://doi.org/10.1016/j.lfs.2018.07.019

Strålin, P., Karlsson, K., Johansson, B. O., & Marklund, S. L. (1995). The interstitium of the human arterial wall contains very large amounts of extracellular superoxide dismutase. Arterioscler Thromb Vasc Biol, 15(11), 2032-2036. doi:10.1161/01.atv.15.11.2032 DOI: https://doi.org/10.1161/01.ATV.15.11.2032

Tomsa, A. M., Alexa, A. L., Junie, M. L., Rachisan, A. L., & Ciumarnean, L. (2019). Oxidative stress as a potential target in acute kidney injury. PeerJ, 7(4), 80-90. doi:10.7717/peerj.8046 DOI: https://doi.org/10.7717/peerj.8046

Wang, J., Zhou, G., Chen, C., Yu, H., Wang, T., Ma, Y., . . . Chai, Z. (2007). Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett, 168(2), 176-185. doi:10.1016/j.toxlet.2006.12.001 DOI: https://doi.org/10.1016/j.toxlet.2006.12.001

Yamanaka, N., Sasaki, N., Tasaki, A., Nakashima, H., Kubo, M., Morisaki, T., . . . Katano, M. (2004). Nuclear factor-kappaB p65 is a prognostic indicator in gastric carcinoma. Anticancer Res, 24(2), 1071-1075.

Zager, R. A. (2015). Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration. Transl Res, 166(5), 485-501. doi:10.1016/j.trsl.2015.06.004 DOI: https://doi.org/10.1016/j.trsl.2015.06.004