Effects of apigenin on the expression levels of B‑cell lymphoma‑2, Fas and Fas ligand in renal ischemia‑reperfusion injury in rats

Liu,Yang; Liu,Xiuheng; Wang,Lei; Du,Yang; Chen,Zhiyuan; Chen,Hui; Guo,Jia; Weng,Xiaodong; Wang,Xiao; Wang,Ming; Wang,Zhishun

doi:10.3892/etm.2017.5241

Effects of apigenin on the expression levels of B‑cell lymphoma‑2, Fas and Fas ligand in renal ischemia‑reperfusion injury in rats

Authors:
- Yang Liu
- Xiuheng Liu
- Lei Wang
- Yang Du
- Zhiyuan Chen
- Hui Chen
- Jia Guo
- Xiaodong Weng
- Xiao Wang
- Ming Wang
- Zhishun Wang
View Affiliations

Affiliations: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: October 2, 2017 https://doi.org/10.3892/etm.2017.5241
Pages: 5345-5354
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the effect and possible mechanism of apigenin on renal ischemia-reperfusion (I/R) injury in rats, as well as in in vitro experiments. In total, 36 rats were subjected to 45 min of renal ischemia, with or without treatment prior to ischemia with different concentrations of apigenin (2, 10 and 50 mg/kg) administered intravenously. All rats were sacrificed at 24 h after I/R injury. The serum creatinine (Cr) and blood urea nitrogen (BUN) levels were analyzed, and histological examination was conducted. In addition, the expression levels of B‑cell lymphoma 2 (Bcl‑2) and Fas/Fas ligand (FasL) were detected by immunohistochemistry, reverse transcription‑quantitative polymerase chain reaction and western blot analysis. For in vitro experiments, the NRK‑52E cell line was employed. The viability, apoptosis and expression levels of Fas, FasL and Bcl‑2 were examined in the culture of NRK‑52E cells following the I/R. The results indicated that apigenin significantly decreased the levels of serum Cr and BUN induced by renal I/R, demonstrating an improvement in renal function. The histological evidence of renal damage associated with I/R was also mitigated by apigenin in vivo. Furthermore, apigenin increased the cell viability and decreased cell apoptosis in the culture of NRK52E after I/R in vitro. Compared with the I/R group, the expression of Bcl‑2 was upregulated and the expression levels of Fas and FasL were downregulated by apigenin at the mRNA and protein levels in vivo and in vitro. In conclusion, apigenin appeared to increase the expression of Bcl‑2 and reduce Fas/FasL expression in renal I/R injury, providing evident protection against renal I/R injury in rats.

View Figures

View References

1	Jang HR, Ko GJ, Wasowska BA and Rabb H: The interaction between ischemia-reperfusion and immune responses in the kidney. J Mol Med (Berl). 87:859–864. 2009. View Article : Google Scholar : PubMed/NCBI
2	Sementilli A and Franco M: Renal acute cellular rejection: Correlation between the immunophenotype and cytokine expression of the inflammatory cells in acute glomerulitis, arterial intimitis, and tubulointerstitial nephritis. Transplant Proc. 42:1671–1676. 2010. View Article : Google Scholar : PubMed/NCBI
3	Di Nardo M, Ficarella A, Ricci Z, Luciano R, Stoppa F, Picardo S, Picca S, Muraca M and Cogo P: Impact of severe sepsis on serum and urinary biomarkers of acute kidney injury in critically ill children: An observational study. Blood Purif. 35:172–176. 2013. View Article : Google Scholar : PubMed/NCBI
4	Levy EM, Viscoli CM and Horwitz RI: The effect of acute renal failure on mortality. A cohort analysis. JAMA. 275:1489–1494. 1996. View Article : Google Scholar : PubMed/NCBI
5	Santos WJ, Zanetta DM, Pires AC, Lobo SM, Lima EQ and Burdmann EA: Patients with ischaemic, mixed and nephrotoxic acute tubular necrosis in the intensive care unit-a homogeneous population? Crit Care. 10:R682006. View Article : Google Scholar : PubMed/NCBI
6	Jia Y, Zhao J, Liu M, Li B, Song Y, Li Y, Wen A and Shi L: Brazilin exerts protective effects against renal ischemia-reperfusion injury by inhibiting the NF-κB signaling pathway. Int J Mol Med. 38:210–216. 2016. View Article : Google Scholar : PubMed/NCBI
7	Birt DF, Hendrich S and Wang W: Dietary agents in cancer prevention: Flavonoids and isoflavonoids. Pharmacol Ther. 90:157–177. 2001. View Article : Google Scholar : PubMed/NCBI
8	Patel D, Shukla S and Gupta S: Apigenin and cancer chemoprevention: Progress, potential and promise (review). Int J Oncol. 30:233–245. 2007.PubMed/NCBI
9	Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, Guttridge DC, Grotewold E and 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. 179:7121–7127. 2007. View Article : Google Scholar : PubMed/NCBI
10	Tsalkidou EG, Tsaroucha AK, Chatzaki E, Lambropoulou M, Papachristou F, Trypsianis G, Pitiakoudis M, Vaos G and Simopoulos C: The effects of apigenin on the expression of Fas/FasL apoptotic pathway in warm liver ischemia-reperfusion injury in rats. Biomed Res Int. 2014:1572162014. View Article : Google Scholar : PubMed/NCBI
11	Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF, et al: Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 373:441–444. 1995. View Article : Google Scholar : PubMed/NCBI
12	Zhao J, Duan S, Zhou J, Sun R, Zhang L and Wang D: Mild hypothermia reduces expression of Fas/FasL and MMP-3 after cerebral ischemia-reperfusion in rats. Iran J Basic Med Sci. 17:454–459. 2014.PubMed/NCBI
13	Del RM, Imam A, DeLeon M, Gomez G, Mishra J, Ma Q, Parikh S and Devarajan P: The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia. J Am Soc Nephrol. 15:41–51. 2004. View Article : Google Scholar : PubMed/NCBI
14	Erkan E, Garcia CD, Patterson LT, Mishra J, Mitsnefes MM, Kaskel FJ and Devarajan P: Induction of renal tubular cell apoptosis in focal segmental glomerulosclerosis: Roles of proteinuria and Fas-dependent pathways. J Am Soc Nephrol. 16:398–407. 2005. View Article : Google Scholar : PubMed/NCBI
15	Gahl RF, Dwivedi P and Tjandra N: Bcl-2 proteins bid and bax form a network to permeabilize the mitochondria at the onset of apoptosis. Cell Death Dis. 7:e24242016. View Article : Google Scholar : PubMed/NCBI
16	Wang Y, Wang W and Qiu E: Protection of oxidative stress induced apoptosis in osteosarcoma cells by dihydromyricetin through down-regulation of caspase activation and up-regulation of BcL-2. Saudi J Biol Sci. 24:837–842. 2017. View Article : Google Scholar : PubMed/NCBI
17	Tsujimoto Y and Shimizu S: Bcl-2 family: Life-or-death switch. FEBS Lett. 466:6–10. 2000. View Article : Google Scholar : PubMed/NCBI
18	Furuichi K, Kokubo S, Hara A, Imamura R, Wang Q, Kitajima S, Toyama T, Okumura T, Matsushima K, Suda T, et al: Fas ligand has a greater impact than TNF-α on apoptosis and inflammation in ischemic acute kidney injury. Nephron Extra. 2:27–38. 2012. View Article : Google Scholar : PubMed/NCBI
19	Zhu MX, Ran B, Feng ZQ and Pan QW: Effects of Rb1 and Rg1 on the expression of Bcl-2, Bax in apoptosis of HK-2 cells induced by the serum of kidney ischemia/reperfusion. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 25:496–499. 2009.(In Chinese). PubMed/NCBI
20	Wang J, Su B, Zhu H, Chen C and Zhao G: Protective effect of geraniol inhibits inflammatory response, oxidative stress and apoptosis in traumatic injury of the spinal cord through modulation of NF-κB and p38 MAPK. Exp Ther Med. 12:3607–3613. 2016. View Article : Google Scholar : PubMed/NCBI
21	Vogt M, Bauer MK, Ferrari D and Schulze-Osthoff K: Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO-1/Fas) ligand expression in microglial cells. FEBS Lett. 429:67–72. 1998. View Article : Google Scholar : PubMed/NCBI
22	Chang WT, Hsieh BS, Cheng HL, Lee KT and Chang KL: Progesterone augments epirubicin-induced apoptosis in HA22T/VGH cells by increasing oxidative stress and upregulating Fas/FasL. J Surg Res. 188:432–441. 2014. View Article : Google Scholar : PubMed/NCBI
23	Bussuan LA, Fagundes DJ, Marks G, Bussuan PM and Teruya R: The role of Fas ligand protein in the oxidative stress induced by azoxymethane on crypt colon of rats. Acta Cir Bras. 25:501–506. 2010. View Article : Google Scholar : PubMed/NCBI
24	Jablonski P, Howden BO, Rae DA, Birrell CS, Marshall VC and Tange J: An experimental model for assessment of renal recovery from warm ischemia. Transplantation. 35:198–204. 1983. View Article : Google Scholar : PubMed/NCBI
25	Gianello P, Squifflet JP, Carlier M, Lambotte L, Ketelslegers JM and Alexandre GP: Atrial natriuretic factor: A protective role after acute renal ischemia? Is there room for it in kidney transplantation? Transpl Int. 3:41–46. 1990. View Article : Google Scholar : PubMed/NCBI
26	Gobé G, Willgoss D, Hogg N, Schoch E and Endre Z: Cell survival or death in renal tubular epithelium after ischemia-reperfusion injury. Kidney Int. 56:1299–1304. 1999. View Article : Google Scholar : PubMed/NCBI
27	Ameisen JC: On the origin, evolution, and nature of programmed cell death: A timeline of four billion years. Cell Death Differ. 9:367–393. 2002. View Article : Google Scholar : PubMed/NCBI
28	Hanlon MG, Gacis ML, Kakakios AM and Kilham H: Investigation of suspected deficient Fas-mediated apoptosis in a father and son. Cytometry. 43:195–198. 2001. View Article : Google Scholar : PubMed/NCBI
29	Kiechle FL and Zhang X: The postgenomic era: Implications for the clinical laboratory. Arch Pathol Lab Med. 126:255–262. 2002.PubMed/NCBI
30	Markström E, Svensson ECh, Shao R, Svanberg B and Billig H: Survival factors regulating ovarian apoptosis-dependence on follicle differentiation. Reproduction. 123:23–30. 2002. View Article : Google Scholar : PubMed/NCBI
31	Müllauer L, Gruber P, Sebinger D, Buch J, Wohlfart S and Chott A: Mutations in apoptosis genes: A pathogenetic factor for human disease. Mutat Res. 488:211–231. 2001. View Article : Google Scholar : PubMed/NCBI
32	Yuan J and Yankner BA: Apoptosis in the nervous system. Nature. 407:802–809. 2000. View Article : Google Scholar : PubMed/NCBI
33	Hashemi M: The study of pentoxifylline drug effects on renal apoptosis and BCL-2 gene expression changes following ischemic reperfusion injury in rat. Iran J Pharm Res. 13:181–189. 2014.PubMed/NCBI
34	Nilsson L, Madsen K, Krag S, Frøkiær J, Jensen BL and Nørregaard R: Disruption of cyclooxygenase type 2 exacerbates apoptosis and renal damage during obstructive nephropathy. Am J Physiol Renal Physiol. 309:F1035–F1048. 2015. View Article : Google Scholar : PubMed/NCBI
35	Li H, Sun JJ, Chen GY, Wang WW, Xie ZT, Tang GF and Wei SD: Carnosic acid nanoparticles suppress liver ischemia/reperfusion injury by inhibition of ROS, Caspases and NF-κB signaling pathway in mice. Biomed Pharmacother. 82:237–246. 2016. View Article : Google Scholar : PubMed/NCBI
36	Liu A, Huang L, Fan H, Fang H, Yang Y, Liu S, Hu J, Hu Q, Dirsch O and Dahmen U: Baicalein pretreatment protects against liver ischemia/reperfusion injury via inhibition of NF-κB pathway in mice. Int Immunopharmacol. 24:72–79. 2015. View Article : Google Scholar : PubMed/NCBI
37	Zweier JL and Talukder MA: The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res. 70:181–190. 2006. View Article : Google Scholar : PubMed/NCBI
38	Lemasters JJ: V. Necrapoptosis and the mitochondrial permeability transition: Shared pathways to necrosis and apoptosis. Am J Physiol. 276:G1–G6. 1999.PubMed/NCBI
39	Bruno A, Siena L, Gerbino S, Ferraro M, Chanez P, Giammanco M, Gjomarkaj M and Pace E: Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adenocarcinoma cell line. Eur J Cancer. 47:2042–2051. 2011. View Article : Google Scholar : PubMed/NCBI
40	Chen C, He H, Luo Y, Zhou M, Yin D and He M: Involvement of Bcl-2 signal pathway in the protective effects of apigenin on Anoxia/Reoxygenation-induced myocardium injury. J Cardiovasc Pharmacol. 67:152–163. 2016. View Article : Google Scholar : PubMed/NCBI
41	Walls KC, Ghosh AP, Ballestas ME, Klocke BJ and Roth KA: bcl-2/Adenovirus E1B 19-kd interacting protein 3 (BNIP3) regulates hypoxia-induced neural precursor cell death. J Neuropathol Exp Neurol. 68:1326–1338. 2009. View Article : Google Scholar : PubMed/NCBI
42	Meier P, Finch A and Evan G: Apoptosis in development. Nature. 407:796–801. 2000. View Article : Google Scholar : PubMed/NCBI
43	Lam M, Dubyak G, Chen L, Nuñez G, Miesfeld RL and Distelhorst CW: Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci USA. 91:pp. 6569–6573. 1994, View Article : Google Scholar : PubMed/NCBI
44	Jin GF, Hurst JS and Godley BF: Hydrogen peroxide stimulates apoptosis in cultured human retinal pigment epithelial cells. Curr Eye Res. 22:165–173. 2001. View Article : Google Scholar : PubMed/NCBI
45	Tsalkidou EG, Tsaroucha AK, Chatzaki E, Lambropoulou M, Papachristou F, Trypsianis G, Pitiakoudis M, Vaos G and Simopoulos C: The effects of apigenin on the expression of Fas/FasL apoptotic pathway in warm liver ischemia-reperfusion injury in rats. Biomed Res Int. 2014:1572162014. View Article : Google Scholar : PubMed/NCBI
46	Malhi H, Gores GJ and Lemasters JJ: Apoptosis and necrosis in the liver: A tale of two deaths? Hepatology. 43 2 Suppl 1:S31–S44. 2006. View Article : Google Scholar : PubMed/NCBI
47	Mor G, Straszewski S and Kamsteeg M: Role of the Fas/Fas ligand system in female reproductive organs: Survival and apoptosis. Biochem Pharmacol. 64:1305–1315. 2002. View Article : Google Scholar : PubMed/NCBI
48	Ortiz A, Lorz C and Egido J: The Fas ligand/Fas system in renal injury. Nephrol Dial Transplant. 14:1831–1834. 1999. View Article : Google Scholar : PubMed/NCBI
49	Hsu SC, Gavrilin MA, Tsai MH, Han J and Lai MZ: p38 mitogen-activated protein kinase is involved in Fas ligand expression. J Biol Chem. 274:25769–25776. 1999. View Article : Google Scholar : PubMed/NCBI