In Vitro Assessment of Anti-inflammatory Effect of Apigenin on Renal Cell Inflammation

Year 2022, , 739 - 745, 28.09.2022

Selen Özsoy , Gül Fatma Yarım

https://doi.org/10.33808/clinexphealthsci.1018335

Abstract

Objective: This study aimed to evaluate in vitro effect of apigenin on anti – and pro-inflammatory cytokines including interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) levels in an in vitro model of renal cell inflammation induced with lipopolysaccharide (LPS).

Methods: For the in vitro renal cell inflammation model, the African green monkey kidney cell line (Vero) was used. Four groups as NC (without any treatment), LPS (Vero cells treated with 10 μg/mL of LPS for 4 hours), API (Vero cells treated with 5 μg/mL of apigenin for 12 hours), and LPS+API (Vero cells treated with 5 μg/mL of apigenin for 12 hours + 10 μg/mL of LPS for 4 hours) was formed. The non-cytotoxic dose of apigenin in Vero cells was evaluated by a cell count test. IL-6, IL-10, TNF-α, and TGF-β concentrations in the cell culture medium were measured by enzyme-linked immunosorbent assay kits. All analyses were performed in four repetitions.

Results: IL-6, IL-10, TNF-α, and TGF-β concentrations of the LPS group increased compared to NC, API, and LPS+API groups (p<0.05). We found that treatment with apigenin led to significant attenuation in the LPS-induced secretion of IL-6, IL-10, TNF-α, and TGF-β in the Vero cell line.

Conclusion: Our findings showed that apigenin significantly reduced LPS-induced IL-6, IL-10, TNF-α, and TGF-β formations in Vero cells. Taken together, these results suggest that apigenin may be a therapeutic candidate for relieving inflammatory renal cell damage. These results need to be supported by in vivo trials and clinical applications.

Keywords

Apigenin, in vitro, lipopolysaccharide, renal cell damage

Supporting Institution

Ondokuz Mayis University

Project Number

PYO.VET.1904.17.014

Thanks

This study was supported by the Scientific Project Management Office of the Ondokuz Mayis University, Samsun, Turkey (PYO.VET.1904.17.014).

References

• [1] Imig J, Ryan M. Immune and inflammatory role in renal disease. Compr Physiol 2013;3(2):957-976.
• [2] Rapa SF, Di Iorio BR, Campiglia P, Heidland A, Marzocco S Inflammation and oxidative stress in chronic kidney disease- potential therapeutic role of minerals, vitamins and plant- derived metabolites. Int J Mol Sci 2019;21(1):263.
• [3] Tbahriti FH, Meknassi D, Moussaoui R, Messaoudi A, Zemour L, Kaddous A, Bouchenak M, Mekki K Inflammatory status in chronic renal failure: The role of homocysteinemia and pro- inflammatory cytokines World J Nephrol 2013;6:31-37.
• [4] Al-Eisa AA, Al Rushood M, Al-Attiyah RJ Urinary excretion of IL-1β, IL-6 and IL-8 cytokines during relapse and remission of idiopathic nephrotic syndrome. J Inflamm Res 2017;23:1-5.
• [5] Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E, Axelrod JH. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008;6:1106-1115.
• [6] Sonkar GK, Singh RG. Evaluation of serum tumor necrosis factor alpha and its correlation with histology in chronic kidney disease, stable renal transplant and rejection cases. Saudi J Kidney Dis Transpl 2009;20:1000-1004.
• [7] Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits- Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M. IL- 10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia-the good, the bad, and the ugly. Kidney Int 2005;67:1216-1233.
• [8] Yeo ES, Hwang JY, Park JE, Choi YJ, Huh KB, Kim WY. Tumor necrosis factor (TNF-alpha) and C-reactive protein (CRP) are positively associated with the risk of chronic kidney disease in patients with type 2 diabetes. Yonsei Med J 2010;51:519-525.
• [9] Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B. Regulation of adiponectin by adipose tissue- derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003;285:E527-533.
• [10] Zhang W, Wang W, Yu H, Zhang Y, Dai Y, Ning C, Tao L, Sun H, Kellems RE, Blackburn MR, Xia Y. Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 2012;59:136-144.
• [11] Idasiak-Piechocka I, Oko A, Pawliczak E, Kaczmarek E, Czekalski S. Urinary excretion of soluble tumour necrosis factor receptor 1 as a marker of increased risk of progressive kidney function deterioration in patients with primary chronic glomerulonephritis. Nephrol Dial Transplant 2010;12:3948- 3956.
• [12] Schnaper HW, Jandeska S, Runyan CE, Hubchak SC, Basu RK, Curley JF, Smith RD, Hayashida T. TGF-beta signal transduction in chronic kidney disease. Front Biosci (Landmark Ed). 2009;1;14:2448-2465.
• [13] Sinuani I, Beberashvili I, Averbukh Z, Sandbank J. Role of IL- 10 in the progression of kidney disease. World J Transplant 2013;3(4):91-98.
• [14] Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013;2013:162750.
• [15] Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, Guttridge DC, Grotewold E, Doseff AI. Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF- kappaB through the suppression of p65 phosphorylation. J Immunol 2007;179:7121-7127.
• [16] Wang J, Liu YT, Xiao L, Zhu L, Wang Q, Yan T. Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway. Inflammation 2014;37:2085-2090.
• [17] Huang CH, Kuo PL, Hsu YL, Chang TT, Tseng HI, Chu YT, Kuo CH, Chen HN, Hung CH. The natural flavonoid apigenin suppresses Th1 – and Th2-related chemokine production by human monocyte THP-1 cells through mitogen-activated protein kinase pathways. J Med Food 2010;13:391-398.
• [18] Cardenas H, Arango D, Nicholas C, Duarte S, Nuovo GJ, He W, Voss OH, Gonzalez-Mejia ME, Guttridge DC, Grotewold E, Doseff AI. Dietary apigenin exerts immune-regulatory activity in vivo by reducing NF-κB Activity, Halting Leukocyte Infiltration and Restoring Normal Metabolic Function. Int J Mol Sci 2016;1:323.
• [19] Huang MY, Chaturvedi LS, Koul S, Koul HK. Oxalate stimulates IL-6 production in HK-2 cells, a line of human renal proximal tubular epithelial cells. Kidney Int 2005;68:497-503.
• [20] Zager RA1, Johnson AC, Geballe A. Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells. Am J Physiol Renal Physiol 2007;293:F1373-1380.
• [21] Smolinski AT, Pestka JJ. Modulation of lipopolysaccharide- induced proinflammatory cytokine production in vitro and in vivo by the herbal constituents apigenin (chamomile), ginsenoside Rb(1) (ginseng) and parthenolide (feverfew). Food Chem Toxicol 2003;41:1381-1390.
• [22] Li B, Hu Y, Zhao Y, Cheng M, Qin H, Cheng T, Wang Q, Peng X, Zhang X. Curcumin attenuates titanium particle-induced inflammation by regulating macrophage polarization in vitro and in vivo. Front Immunol 2017;31;8:55.
• [23] Qian Q. Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease. Contrib Nephrol 2017;191:72-83.
• [24] Impellizzeri D, Bruschetta G, Ahmad A, Crupi R, Siracusa R, Di Paola R, Paterniti I, Prosdocimi M, Esposito E, Cuzzocrea S. Effects of palmitoylethanolamide and silymarin combination treatment in an animal model of kidney ischemia and reperfusion. Eur J Pharmacol 2015;762:136-149.
• [25] Kandemir FM, Kucukler S, Eldutar E, Caglayan C, Gulcin I. Chrysin protects rat kidney from paracetamol-induced oxidative stress, inflammation, apoptosis, and autophagy: A Multi-Biomarker Approach. Sci Pharm 2017;85:4.
• [26] Ahmad ST, Arjumand W, Nafees S, Seth A, Ali N, Rashid S, Sultana S. Hesperidin alleviates acetaminophen induced toxicity in Wistar rat by abrogation of oxidative stress, apoptosis and inflammation. Toxicol Lett 2012;208:149-161.
• [27] Fanti P, Asmis R, Stephenson TJ, Sawaya BP, Franke AA. Positive effect of dietary soy in ESRD patients with systemic inflammation—correlation between blood levels of the soy isoflavones and the acute-phase reactants. Nephrol Dial Transplant 2006;21:2239-2246.
• [28] Ali BH, Adham SA, Al Za’abi M, Waly MI, Yasin J, Nemmar A, Schupp N. Ameliorative effect of chrysin on adenine-induced chronic kidney disease in rats. PLoS One 2015;10:e0125285.
• [29] Prince PD, Lanzi CR, Toblli JE, Elesgaray R, Oteiza PI, Fraga CG, Galleano M. Dietary (-)-epicatechin mitigates oxidative stress, NO metabolism alterations, and inflammation in renal cortex from fructose-fed rats. Free Radic Biol Med 2016;90:35-46.
• [30] Liu CM, Sun YZ, Sun JM, Ma JQ, Cheng C. Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-κB pathway. Biochim Biophys Acta 2012;1820:1693-1703.
• [31] Chtourou Y, Aouey B, Aroui S, Kebieche M, Fetoui H. Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. Chem Biol Interact 2016;243:1-9.
• [32] Elmarakby AA, Ibrahim AS, Faulkner J, Mozaffari MS, Liou GI, Abdelsayed R. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol 2011;55:149-156.
• [33] Wang W, Zhou PH, Xu CG, Zhou XJ, Hu W, Zhang J. Baicalein attenuates renal fibrosis by inhibiting inflammation via down- regulating NF-κB and MAPK signal pathways. J Mol Histol 2015;46:283-290.
• [34] Malik S, Bhatia J, Suchal K, Gamad N, Dinda AK, Gupta YK, Arya DS. Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti-oxidant, anti-inflammatory and anti-apoptotic effects. Exp Toxicol Pathol 2015;67:427-433.
• [35] Zager RA, Johnson AC, Geballe A. Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells. Am J Physiol Renal Physiol 2007;293:1373-1380.
• [36] Funakoshi-Tago M, Nakamura K, Tago K, Mashino T, Kasahara T Anti-inflammatory activity of structurally related flavonoids, Apigenin, luteolin and fisetin. Int Immunopharmacol 2011;11:1150-1159.
• [37] He X, Li C, Wei Z, Wang J, Kou J, Liu W, Shi M, Yang Z, Fu Y. Protective role of apigenin in cisplatin-induced renal injury. Eur J Pharmacol 2016;789:215-221.
• [38] Arango D, Diosa-Toro M, Rojas-Hernandez LS, Cooperstone JL, Schwartz SJ, Mo X, Jiang J, Schmittgen TD, Doseff AI. Dietary apigenin reduces LPS-induced expression of miR-155 restoring immune balance during inflammation. Mol Nutr Food Res 2015;59:763-772.