Investigation of the effect of Chloroquine on Adriamycin-induced kidney damage

Abstract

Although Adriamycin (ADR) is an important anticancer drug used in chemotherapy, it causes nephrotoxicity. The inflammation pathway has an important role in ADR-induced nephrotoxicity. Chloroquine (CLQ), which is used as an antimalarial drug, is used in many diseases. Also, CLQ is known as an anti-inflammatory. In this study, we aimed to investigate the effect of CLQ against nephrotoxicity caused by ADR through the inflammatory pathway. Groups were formed as follows; Control (n = 8), CLQ (n = 8) 50 mg / kg intraperitoneally (i.p.) per day, ADR (n = 8) 2 mg / kg i.p. every 3 days, ADR + CLQ (n = 8) 2mg / kg / i.p. ADR + 50 mg / kg / i.p. CLQ. The experiment took a total of 30 days. At the end of the experiment, kidney tissues were taken from the rats under anesthesia. After fixation in the removed kidney tissues, the tissues were embedded in paraffin by histological methods. Sections were taken from kidney tissues. Renal tissue histopathology and Tumor necrosis factor-alpha (TNF-α) and Nuclear factor-κB p65 (NF-κB p65) immunoreactivities were evaluated. When the kidney tissue was examined, it was seen that damage was caused by ADR. In addition, it was observed that TNF-α and NF-κB p65 immunoreactivities in the kidney significantly increased in the ADR group (p <0.05). Damage and inflammatory markers were found to be decreased in the ADR + CLQ group (p <0.05). Chemotherapeutically administered ADR appears to cause nephrotoxicity. CLQ administered was found to reduce this toxicity. As a result, we showed that the damage caused by ADR-induced nephrotoxicity decreased with the application of CLQ through the TNF-α and NF-κB p65 inflammation pathway.

Keywords

• Adriamycin
• Chloroquine
• Inflammation
• Kidney

References

1. 1. Wei MG, He WM, Lu X, et al. JiaWeiDangGui Decoction Ameliorates Proteinuria and Kidney Injury in Adriamycin-Induced Rat by Blockade of TGF-β/Smad Signaling. Evidence-based complementary and alternative medicine : eCAM. 2016;2016:5031890.
2. 2. Rybi-Szumińska A, Wasilewska A, Michaluk-Skutnik J, et al. Are oxidized low-density lipoprotein and C-reactive protein markers of atherosclerosis in nephrotic children? Irish journal of medical science. 2015;184(4):775-80.
3. 3. Pillai VB, Kanwal A, Fang YH, et al. Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice. Oncotarget. 2017;8(21):34082-98.
4. 4. Liang CL, Zhang PC, Wu JB, et al. Zhen-wu-tang attenuates Adriamycin-induced nephropathy via regulating AQP2 and miR-92b. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019;109:1296-305.
5. 5. Yokochi T, Robertson KD. Doxorubicin inhibits DNMT1, resulting in conditional apoptosis. Molecular pharmacology. 2004;66(6):1415-20.
6. 6. Liu LL, Li QX, Xia L, et al. Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats. Toxicology. 2007;231(1):81-90.
7. 7. Zordoky BN, Anwar-Mohamed A, Aboutabl ME, et al. Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver. Drug metabolism and disposition: the biological fate of chemicals. 2011;39(8):1440-50.
8. 8. Rivankar S. An overview of doxorubicin formulations in cancer therapy. Journal of cancer research and therapeutics. 2014;10(4):853-8.

9. 9. Szalay CI, Erdélyi K, Kökény G, et al.Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain. PloS one. 2015;10(6):e0127090.
10. 10. Zhu MM, Wang L, Yang D, et al. Wedelolactone alleviates doxorubicin-induced inflammation and oxidative stress damage of podocytes by IκK/IκB/NF-κB pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2019;117:109088.
11. 11. Sahraoui A, Dewachter C, de Medina G, et al.Myocardial Structural and Biological Anomalies Induced by High Fat Diet in Psammomys obesus Gerbils. PloS one. 2016;11(2):e0148117.
12. 12. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology. 2001;11(9):372-7.
13. 13. Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochemical pharmacology. 2004;68(6):1255-67.
14. 14. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109 Suppl:S81-96.
15. 15. Borgohain MP, Lahkar M, Ahmed S, et al. Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat. Basic & clinical pharmacology & toxicology. 2017;120(5):442-9.
16. 16. Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Seminars in immunology. 2014;26(3):253-66.
17. 17. Pozniak PD, White MK, Khalili K. TNF-α/NF-κB signaling in the CNS: possible connection to EPHB2. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2014;9(2):133-41.
18. 18. Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. The Journal of antimicrobial chemotherapy. 2015;70(6):1608-21.
19. 19. Long L, Yang X, Southwood M, et al.Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circulation research. 2013;112(8):1159-70.
20. 20. Shivakumar P, Rani MU, Reddy AG, et al. A study on the toxic effects of Doxorubicin on the histology of certain organs. Toxicology international. 2012;19(3):241-4.
21. 21. Kaymak E, Akin AT, Tufan E, et al. The effect of chloroquine on the TRPC1, TRPC6, and CaSR in the pulmonary artery smooth muscle cells in hypoxia‐induced experimental pulmonary artery hypertension. Journal of biochemical and molecular toxicology.e22636.
22. 22. Park EJ, Kwon HK, Choi YM, , et al.Doxorubicin induces cytotoxicity through upregulation of pERK-dependent ATF3. PloS one. 2012;7(9):e44990.
23. 23. Wang B, Guo H, Ling L, et al. The Chronic Adverse Effect of Chloroquine on Kidney in Rats through an Autophagy Dependent and Independent Pathways. Nephron. 2020;144(2):96-108.
24. 24. Mauthe M, Orhon I, Rocchi C, , et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-55.
25. 25. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clinical immunology (Orlando, Fla). 2020;214:108393.
26. 26. Guo NF, Cao YJ, Chen X, et al.Lixisenatide protects doxorubicin-induced renal fibrosis by activating wNF-κB/TNF-α and TGF-β/Smad pathways. European review for medical and pharmacological sciences. 2019;23(9):4017-26.
27. 27. Kim DR, Lee SY, Kim JS, et al. Ameliorating Effect of Gemigliptin on Renal Injury in Murine Adriamycin-Induced Nephropathy. 2017;2017:7275109.
28. 28. Cortez M, Carmo LS, Rogero MM, et al. A high-fat diet increases IL-1, IL-6, and TNF-α production by increasing NF-κB and attenuating PPAR-γ expression in bone marrow mesenchymal stem cells. Inflammation. 2013;36(2):379-86.
29. 29. Reiterer G, Toborek M, Hennig B. Quercetin protects against linoleic acid-induced porcine endothelial cell dysfunction. The Journal of nutrition. 2004;134(4):771-5.
30. 30. Neale TJ, Rüger BM, Macaulay H, et al.Tumor necrosis factor-alpha is expressed by glomerular visceral epithelial cells in human membranous nephropathy. The American journal of pathology. 1995;146(6):1444-54.
31. 31. Liu T, Zhang L, Joo D, et al. NF-κB signaling in inflammation. Signal transduction and targeted therapy. 2017;2:17023.
32. 32. Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunological reviews. 2006;210:171-86.
33. 33. Altınkaynak Y, Kural B, Akcan BA, et al. Protective effects of L-theanine against doxorubicin-induced nephrotoxicity in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;108:1524-34.
34. 34. Entezari Heravi N, Hosseinian S, Naji Ebrahimi Yazd Z, et al.Doxorubicin-induced renal inflammation in rats: Protective role of Plantago major. Avicenna journal of phytomedicine. 2018;8(2):179-87.
35. 35. Zhang Q, Wu G, Guo S, et al.Effects of tristetraprolin on doxorubicin (adriamycin)-induced experimental kidney injury through inhibiting IL-13/STAT6 signal pathway. American journal of translational research. 2020;12(4):1203-21.
36. 36. Wang Z, Huang W, Li H, et al.Synergistic action of inflammation and lipid dysmetabolism on kidney damage in rats. Renal failure. 2018;40(1):175-82.
37. 37. Liu WJ, Luo MN, Tan J, et al. Autophagy activation reduces renal tubular injury induced by urinary proteins. Autophagy. 2014;10(2):243-56.
38. 38. Havasi A, Dong Z. Autophagy and Tubular Cell Death in the Kidney. Seminars in nephrology. 2016;36(3):174-88.
39. 39. Magwere T, Naik YS, Hasler JA. Effects of chloroquine treatment on antioxidant enzymes in rat liver and kidney. Free radical biology & medicine. 1997;22(1-2):321-7.
40. 40. Duan X, Kong Z, Mai X, et al.Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney. Redox biology. 2018;16:414-25.