Email this article Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-kB pathways in mice
, Maryam Salehcheh, Hadi Kalantar, Layasadat Khorsandi, Mohammad Rashno, Masoud Mahdavinia Abstract
Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice.
Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7th to the 14th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7th to the 14th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed.
Findings/Results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants.
Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-κB/Nox4 pathway.
Keywords
Full Text:
PDFReferences
Al-Forkan M, Wali FB, Khaleda L, Alam MJ, Chowdhury RH, Datta A, et al. Association of arsenic-induced cardiovascular disease susceptibility with genetic polymorphisms. Sci Rep. 2021;11(1):6263,1-16.DOI: 10.1038/s41598-021-85780-8.
Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M. Toxic mechanisms of five heavy metals: mercury, lead, chromium, cadmium, and arsenic. Front Pharmacol. 2021;12:643972.DOI: 10.3389/fphar.2021.643972.
Kwiatkowska E, Domanski L, Dziedziejko V, Kajdy A, Stefanska K, Kwiatkowski S. The mechanism of drug nephrotoxicity and the methods for preventing kidney damage. Int J Mol Sci. 2021;22(11):6109,1-16.DOI: 10.3390/ijms22116109.
Robles-Osorio ML, Sabath-Silva E, Sabath E. Arsenic-mediated nephrotoxicity. Ren Fail. 2015;37(4):542-547.DOI: 10.3109/0886022X.2015.1013419.
Gong X, Ivanov VN, Davidson MM, Hei TK. Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death. Arch Toxicol. 2015;89:1057-1070.DOI: 10.1007/s00204-014-1302-y.
Saintilnord WN, Fondufe-Mittendorf Y. Arsenic-induced epigenetic changes in cancer development. Semin Cancer Biol. 2021;76:195-205.DOI: 10.1016/j.semcancer.2021.03.019.
Ahangarpour A, Zeidooni L, Samimi A, Alboghobeish S, Khorsandi LS, Moradi M. Chronic exposure to arsenic and high fat diet additively induced cardiotoxicity in male mice. Res Pharm Sci. 2018;13(1):47-56.DOI: 10.4103/1735-5362.220967.
Tsai HJ, Hung CH, Wang CW, Tu HP, Li CH, Tsai CC, et al. Associations among heavy metals and proteinuria and chronic kidney disease. Diagnostics (Basel). 2021;11(2):282,1-12.DOI: 10.3390/diagnostics11020282.
Shafiee F, Safaeian L, Gorbani F. Protective effects of protocatechuic acid against doxorubicin- and arsenic trioxide-induced toxicity in cardiomyocytes. Res Pharm Sci. 2023;18(2):149-158. DOI: 10.4103/1735-5362.367794.
Elsharkawy AM, Mann DA. Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis. Hepatology. 2007;46(2):590-597.DOI: 10.1002/hep.21802.
O'Dea E, Hoffmann A. The regulatory logic of the NF-κB signaling system. Cold Spring Harb Perspect Biol. 2010;2(1):a000216,1-12.DOI: 10.1101/cshperspect.a000216.
Jalili C, Korani M, Pazhouhi M, Ghanbari A, Zhaleh M, Davoudi S, et al. Protective effect of gallic acid on nicotine-induced testicular toxicity in mice. Res Pharm Sci. 2021;16(4):414-424.DOI: 10.4103/1735-5362.319579.
Kopustinskiene DM, Masteikova R, Lazauskas R, Bernatoniene J. Cannabis sativa L. bioactive compounds and their protective role in oxidative stress and inflammation. Antioxidants. 2022;11(4):660,1-12. DOI: 10.3390/antiox11040660.
Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam RJ. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. 2009;30(10):515-527.DOI: 10.1016/j.tips.2009.07.006.
Jean‐Gilles L, Braitch M, Latif ML, Aram J, Fahey AJ, Edwards LJ, et al. Effects of pro‐inflammatory cytokines on cannabinoid CB 1 and CB 2 receptors in immune cells. Acta Physiol (Oxf). 2015;214(1):63-74.DOI: 10.1111/apha.12474.
Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther. 2005;314(2):780-788.DOI: 10.1124/jpet.105.085779.
Du Y, Xu T, Luo D, Wang Y, Yin H, Liu C, et al. Perfluorooctane sulfonate-induced apoptosis in kidney cells by triggering the NOX4/ROS/JNK axis and antagonism of cannabidiol. Environ Toxicol. 2023;38(7):1651-1664.DOI: 10.1002/tox.23794. Epub 2023 Mar 29.
Pan H, Mukhopadhyay P, Rajesh M, Patel V, Mukhopadhyay B, Gao B, et al. Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther. 2009;328(3):708-714.DOI:10.1124/jpet.108.147181.
Nagata S. Apoptosis and clearance of apoptotic cells. Annu Rev immunol. 2018;36:489-517.DOI: 10.1146/annurev-immunol-042617-053010.
Yang y. Ginsenoside Rg1 attenuates arsenic-induced mice nephrotoxicity via the activated HO-1/mTOR-associated apoptosis or autophagy signaling. Sci Open. 2021;1-35.DOI: 10.14293/S2199-1006.1.SOR-.PPSYGZI.v1.
Emami Bistgani Z, Siadat SA, Bakhshandeh A, Pirbalouti AG, Hashemi M. Interactive effects of drought stress and chitosan application on physiological characteristics and essential oil yield of Thymus daenensis Celak. 2017;5(5):407-415.DOI: 10.1016/j.cj.2017.04.003.
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82(1):70-77.DOI: 10.1016/0003-9861(59)90090-6.
Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta. 1978;90(1):37-43.DOI: 10.1016/0009-8981(78)90081-5.
Shangari N, O'Brien PJ. Catalase activity assays. Toxicol. 2006;7(1):1-15.DOI: 10.1002/0471140856.tx0707s27.
van der Kamp MW, Mulholland AJ. Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology. Biochemistry. 2013;52(16):2708-2728.DOI: 10.1021/bi400215w.
Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci. 2011;123(2):305-332.DOI: 10.1093/toxsci/kfr184.
Rana MN, Tangpong J, Rahman MM. Toxicodynamics of lead, cadmium, mercury and arsenic-induced kidney toxicity and treatment strategy: a mini review. Toxicol Rep. 2018;5:704-713.DOI: 10.1016/j.toxrep.2018.05.012.
Dutta S, Saha S, Mahalanobish S, Sadhukhan P, Sil PC. Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice. Food Chem Toxicol. 2018;118:303-316.DOI: 10.1016/j.fct.2018.05.032.
Wan F, Zhong G, Wu S, Jiang X, Liao J, Zhang X, et al. Arsenic and antimony co-induced nephrotoxicity via autophagy and pyroptosis through ROS-mediated pathway in vivo and in vitro. Ecotoxicol Environ Saf. 2021;221:112442,1-12. DOI: 10.1016/j.ecoenv.2021.112442.
Kuret T, Kreft ME, Romih R, Veranič P. Cannabidiol as a promising therapeutic option in IC/BPS: in vitro evaluation of its protective effects against inflammation and oxidative stress. Int J Mol Sci. 2023;24(5):5055,1-19.DOI: 10.3390/ijms24055055.
Hofmann W, Ehrich JH, Guder WG, Keller F, Scherberich JE. Diagnostic pathways for exclusion and diagnosis of kidney diseases. Clin lab. 2012;58(9-10):871-889.PMID: 23163102.
Hsu CY, Chinchilli VM, Coca S, Devarajan P, Ghahramani N, Go AS, et al. Post-acute kidney injury proteinuria and subsequent kidney disease progression: the assessment, serial evaluation, and subsequent sequelae in acute kidney injury (ASSESS-AKI) study. JAMA Intern Med. 2020;180(3): 402-410.DOI: 10.1001/jamainternmed.2019.6390.
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1): 245-313.DOI: 10.1152/physrev.00044.2005.
Sedeek M, Nasrallah R, Touyz RM, Hebert RL. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe. J Am Soc Nephrol. 2013;24(10):1512-1518.DOI: 10.1681/ASN.2012111112.
Straub AC, Clark KA, Ross MA, Chandra AG, Li S, Gao X, et al. Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide. J Clin Invest. 2008;118(12):3980-3989.DOI: 10.1172/JCI35092.
Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Cohen SM. Effects of co-administration of dietary sodium arsenite and an NADPH oxidase inhibitor on the rat bladder epithelium. Toxicology. 2009;261(1-2):41-46.DOI: 10.1016/j.tox.2009.04.042.
Yang Q, Wu Fr, Wang Jn, Gao L, Jiang L, Li HD, et al. Nox4 in renal diseases: an update. Free Radic Biol Med. 2018;124:466-472.DOI: 10.1016/j.freeradbiomed.2018.06.042.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.