Naringin attenuates diabetic retinopathy by inhibiting inflammation, oxidative stress and NF-κB activation in vivo and in vitro

Document Type : Original Article

Authors

1 Department of Anatomy, Histology and Embryology, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, People’s Republic of China

2 Department of Anatomy, Jinzhou Medical University, Jinzhou, Liaoning 121001, People’s Republic of China

3 Department of Respiratory Medicine, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, People’s Republic of China

4 Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, People’s Republic of China

Abstract

Objective(s): Naringin, an essential flavonoid, inhibits inflammatory response and oxidative stress in diabetes. However, whether naringin has beneficial effects on diabetic retinopathy (DR) remains unknown.
Materials and Methods: Streptozotocin (STZ, 65 mg/kg) was intraperitoneally injected into male rats (8 weeks old weighting 200-250 g) to establish diabetic model, then naringin (20, 40 or 80 mg/kg/day) was intraperitoneally injected into the diabetic rats for twelve weeks. Glial fibrillary acidic protein (GFAP) level, thickness of ganglion cell layer (GCL) and ganglion cell counts were assessed in diabetic retina in vivo. Naringin (50 μM) that significantly inhibited high glucose (HG, 25 mM)-induced cell proliferation was used to treat rat Muller cell line (rMC1) in vitro. Inflammatory response, oxidative stress and activation of nuclear factor kappa B (NF-κB) p65 were evaluated in retina in vivo and in rMC1 cells in vitro.
Results: Naringin alleviated DR symptoms as evidenced by the increased retinal ganglion cells and decreased GFAP level in rat retina. Naringin exhibited anti-inflammatory and antioxidative effects as confirmed by the down-regulated pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and the up-regulated antioxidants, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in DR rats. Moreover, we found that naringin inhibited HG-induced proliferation, abnormal inflammatory response and oxidative stress in rMC1 cells. In addition, the enhanced nuclear translocation of NF-κB p65 in diabetic rat retina and HG-induced rMC1 cells was suppressed by naringin.
Conclusion: Naringin attenuates inflammatory response, oxidative stress and NF-κB activation in experimental models of DR.

Keywords


1. Manna P, Das J, Ghosh J, Sil PC. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. Free Radic Biol Med 2010; 48:1465-1484.
2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1978; 1:168-188.
3. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.
4. Klein R KB, Moss SE. Visual impairment in diabetes. Ophthalmology 1984; 91:1–9.
5. Yau JW, Rogers S, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35:556-564.
6. Chew EY, Ferris FL, Csaky KG, Murphy RP, Agrón E, Thompson DJS, et al. The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy. Ophthalmology 2003; 110:1683-1689.
7. Early Treatment Diabetic Retinopathy Study Research Group. Early Photocoagulation for Diabetic Retinopathy. Ophthalmology 1991; 98:766-785.
8. Chang YH, Chen PL, Tai MC, Chen CH, Lu DW, Chen JT. Hyperbaric oxygen therapy ameliorates the blood–retinal. Clin Exp Ophthalmol 2006; 24:584-589.
9. Yue S, Dong Y. Drug treatment of diabetic retinopathy. China Med Herald 2007; 32:005.
10. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010; 376:124–136.
11. Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J 2004; 18:1450-1452.
12. Frey T, Antonetti DA. Alterations to the blood-retinal barrier in diabetes: cytokines and reactive oxygen species. Antioxid Redox Signal 2011; 15:1271-1284.
13. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107:1058-1070.
14. Mahmoud AM, Ashour MB, Abdel-Moneim A, Ahmed OM. Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J Diabetes Complications 2012; 26:483-490.
15. Mahoney SE, Loprinzi PD. Influence of flavonoid-rich fruit and vegetable intake on diabetic retinopathy and diabetes-related biomarkers. J Diabetes Complications 2014; 28:767-771.
16. Falcone Ferreyra ML, Emiliani J, Rodriguez EJ, Campos-Bermudez VA, Grotewold E, Casati P. The identification of maize and Arabidopsis type I flavone synthases links flavones with hormones and biotic interactions. Plant Physiol 2015; 169:1090-1107.
17. Schijlen EG, Ric de Vos CH, van Tunen AJ, Bovy AG. Modification of flavonoid biosynthesis in crop plants. Phytochemistry 2004; 65:2631-2648.
18. Igual M, Garcia-Martinez E, Camacho MM, Martinez-Navarrete N. Jam processing and storage effects on β-carotene and flavonoids content in grapefruit. J Funct Foods 2013; 5:736-744.
19. Banjerdpongchai R, Wudtiwai B, Khaw-On P, Rachakhom W, Duangnil N, Kongtawelert P. Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biol 2016; 37:227-237.
20. Castillo J, Benavente-Garcia O, Del Rio JA. Study and optimization of citrus flavanone and flavones elucidation by reverse phase HPLC with several mobile phases: influence of the structural characteristics. J Liq Chromatogr Relat Technol 1994; 17:1497-1523.
21. Pierre M, Emile MG, Jacques E. Column liquid chromatographic determination of flavanone glycosides in Citrus_ Application to grapefruit and sour orange juice adulterations. J Chromatogr 1993; 634:129-134.
22. Ali MM, El Kader MA. The influence of naringin on the oxidative state of rats with streptozotocin-induced acute hyperglycaemia. Z Naturforsch C 2004; 59:726-733.
23. Lambev I, Krushkov I, Zheliazkov D, Nikolov N. Antiexudative effect of naringin in experimental pulmonary edema and peritonitis. Eksp Med Morfol 1979; 19:207-212.
24. Martin MJ, Marhuenda E, Perez-Guerrero C, Franco JM. Antiulcer effect of naringin on gastric lesions induced by ethanol in rats. Pharmacology 1994; 49:144-150.
25. So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 1996; 26:167-181.
26. Ratana B, Benjawan W, Patompong K. Induction of human hepatocellular carcinoma HepG2 cell apoptosis by naringin. Asian Pac J Cancer P 2016; 17:3289-3294.
27. Kandhare AD, Ghosh P, Bodhankar SL. Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact 2014; 219:101-112.
28. Kandhare AD, Raygude KS, Ghosh P, Ghule AE, Bodhankar SL. Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia 2012; 83:650-659.
29. Chen F, Zhang N, Ma X, Huang T, Shao Y, Wu C, et al. Naringin alleviates diabetic kidney disease through inhibiting oxidative stress and inflammatory reaction. PLoS One 2015; 10:e0143868.
30. Barber AJ. A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsycho-pharmacol Biol Psychiatry 2003; 27:283-290.
31. Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, et al. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 1998; 47:815-820.
32. van Dijk HW, Verbraak FD, Kok PH, Garvin MK, Sonka M, Lee K, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest Ophthalmol Vis Sci 2010; 51:3660-3665.
33. Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy. Exp Diabetes Res 2007; 2007:43603.
34. Kumar B, Gupta SK, Srinivasan BP, Nag TC, Srivastava S, Saxena R, et al. Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res 2013; 87:65-74.
35. Bucolo C, Leggio GM, Drago F, Salomone S. Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Biochem Pharmacol 2012; 84:88-92.
36. Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res 2011; 30:343-358.
 
 
37. Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother 2005; 59:365-373.
38. Li N, Karin, M. Is NF-κB the sensor of oxidative stress? FASEB J 1999; 13:1137-1143.
39. Liu Y, Wu H, Nie YC, Chen JL, Su WW, Li PB. Naringin attenuates acute lung injury in LPS-treated mice by inhibiting NF-kappaB pathway. Int Immunopharmacol 2011; 11:1606-1612.
40. Chtourou Y, Aouey B, Kebieche M, Fetoui H. Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-kappaB and P53 signaling pathways. Chem Biol Interact 2015; 239:76-86.
41. Sharma AK, Bharti S, Ojha S, Bhatia J, Kumar N, Ray R,  et al. Up-regulation of PPARgamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br J Nutr 2011; 106:1713-1723.