Abstract
Hyperglycaemia-mediated oxidative stress plays an imperative role in the progression of diabetic nephropathy. NF-kB is an important transcription factor in eukaryotes which regulates a diverse array of cellular process, including inflammation, immunological response, apoptosis, growth and development. Increased expression of NF-kB plays a vital role in the pathogenesis of many inflammatory diseases including diabetic nephropathy. Hence, the present study was designed to explore the nephroprotective nature of diosmin by assessing the various biochemical parameters, markers of oxidative stress and proinflammatory cytokine levels in alloxan-induced diabetic Wistar rats. Type 2 diabetes was induced in Wistar rats by single intraperitoneal injection of alloxan (120 mg/kg body weight). Seventy-two hours after the conformation of diabetes (blood glucose level ≥ 250 mg/dl), the rats were segregated into four groups, each group having six animals. Diabetic rats were treated with diosmin at a dose of 50 mg and 100 mg/kg body weight respectively. After the 28th day of treatment, rats were sacrificed, blood serum, plasma and kidney tissue were collected for various biochemical analysis. Inflammatory cytokine levels were measured through ELISA kit. Diosmin treatment produces significant reduction in the blood glucose and plasma insulin level and increases the body weight when compared with diabetic rats. Elevated level of malondialdehyde (MDA) and decrease levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and nitric oxide (NO) were significantly restored after 28 days of diosmin treatment. Diosmin treatment group also restores the normal architecture of the kidney tissue which was confirmed by histopathological examination. Moreover, oral administration of diosmin shows a significant normalization in the level of NF-kB, proving its pivotal role in maintaining renal function. The above ameliorative effects were more pronounced with diosmin at a dose of 100 mg/kg body weight. The above results permit us to conclude that treatment with diosmin halts hyperglycaemia-mediated oxidative stress and decline in pro-inflammatory cytokines and thus has beneficial anti-diabetic activity.
Similar content being viewed by others
References
Akcilar, R., S. Turgut, V. Caner, A. Akcilar, C. Ayada, et al. 2015. The effects of apelin treatment on a rat model of type 2 diabetes. Advanced Medical Science 60: 94–100.
Palsamy, P., and S. Subramanian. 2009. Modulatory effects of resveratrol on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. Chemico-Biological Interactions 179: 356–362.
Abedi Gaballu, F., Abedi Gaballu, Y., Moazenzade Khyavy, O., Mardomi, A., Ghahremanzadeh, K., et al. 2015. Effects of a triplex mixture of Peganum harmala, Rhus coriaria, and Urtica dioica aqueous extracts on metabolic and histological parameters in diabetic rats. Pharmaceutical Biology: 1–6.
Gwarzo, M.Y., J.H. Ahmadu, M.B. Ahmad, and A.U. Dikko. 2013. Serum glucose and malondialdehyde levels in alloxan induced diabetic rats supplemented with methanolic extract of tacazzea apiculata. International Journal of Biomedical Sciences 10: 236–242.
Wild, S., G. Roglic, A. Green, R. Sicree, and H. King. 2004. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053.
Kumkrai, P., S. Kamonwannasit, and N. Chudapongse. 2014. Cytoprotective and anti-diabetic effects of Derris reticulata aqueous extract. Journal of Physiology and Biochemistry 70: 675–684.
Shaw, J.E., R.A. Sicree, and P.Z. Zimmet. 2010. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Research and Clinical Practice 87: 4–14.
Mohan, V., P. Mathur, R. Deepa, M. Deepa, D.K. Shukla, et al. 2008. Urban rural differences in prevalence of self-reported diabetes in India—the WHO-ICMR Indian NCD risk factor surveillance. Diabetes Research and Clinical Practice 80: 159–168.
Gerich, J.E. 2003. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Archives of Internal Medicine 163: 1306–1316.
Montero, R.M., A. Covic, L. Gnudi, and D. Goldsmith. 2016. Diabetic nephropathy: what does the future hold? International Urology and Nephrology 48: 99–113.
Das, K. K., Razzaghi-Asl, N., Tikare, S. N., Di Santo, R., Costi, R., et al. 2016. Hypoglycemic activity of curcumin synthetic analogues in alloxan-induced diabetic rats. Journal of Enzyme Inhibition and Medicinal Chemistry: 1–7.
Fu, J., J. Yuan, N. Zhang, B. Gao, G. Fu, et al. 2012. Anti-diabetic activities of Acanthopanax senticosus polysaccharide (ASP) in combination with metformin. International Journal of Biological Macromolecules 50: 619–623.
Samad, A., M.S. Shams, Z. Ullah, M. Wais, I. Nazish, et al. 2009. Status of herbal medicines in the treatment of diabetes: a review. Current Diabetes Reviews 5: 102–111.
Ibeh, B.O., and M.I. Ezeaja. 2011. Preliminary study of antidiabetic activity of the methanolic leaf extract of Axonopus compressus (P. Beauv) in alloxan-induced diabetic rats. Journal of Ethnopharmacology 138: 713–716.
Fan, Y., Q. He, A. Luo, and M. Wang. 2015. Characterization and antihyperglycemic activity of a polysaccharide from dioscorea opposita thumb roots. International Journal of Molecular Sciences 16: 6391–6401.
Hayat, M.M., S. Sarwar, S. Anjum, M. Uzair, H.M. Farhan Rasheed, et al. 2014. Anti-diabetic and spasmolytic potential of Farsetia hamiltonii Royle from Cholistan desert. Journal of Ethnopharmacology 156: 347–352.
Dholakiya, S.L., and K.E. Benzeroual. 2011. Protective effect of diosmin on LPS-induced apoptosis in PC12 cells and inhibition of TNF-alpha expression. Toxicology In Vitro 25: 1039–1044.
Middleton Jr., E., C. Kandaswami, and T.C. Theoharides. 2000. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological Reviews 52: 673–751.
Matteucci, E., and O. Giampietro. 2000. Oxidative stress in families of type 1 diabetic patients. Diabetes Care 23: 1182–1186.
Firuzi, O., R. Miri, M. Tavakkoli, and L. Saso. 2011. Antioxidant therapy: current status and future prospects. Current Medicinal Chemistry 18: 3871–3888.
Sila, A., Z. Kamoun, Z. Ghlissi, M. Makni, M. Nasri, et al. 2015. Ability of natural astaxanthin from shrimp by-products to attenuate liver oxidative stress in diabetic rats. Pharmacological Reports 67: 310–316.
Di Marco, E., J.C. Jha, A. Sharma, J.L. Wilkinson-Berka, K.A. Jandeleit-Dahm, et al. 2015. Are reactive oxygen species still the basis for diabetic complications? Clinical Science (London) 129: 199–216.
Arab, H.H., S.A. Salama, H.A. Omar, S.A. el Arafa, and I.A. Maghrabi. 2015. Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One 10, e0122417.
Park, N.Y., S.K. Park, and Y. Lim. 2011. Long-term dietary antioxidant cocktail supplementation effectively reduces renal inflammation in diabetic mice. British Journal of Nutrition 106: 1514–1521.
Patel, S., and D. Santani. 2009. Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacological Reports 61: 595–603.
Okamoto, K., D.P. Martin, J.D. Schmelzer, Y. Mitsui, and P.A. Low. 2001. Pro- and anti-inflammatory cytokine gene expression in rat sciatic nerve chronic constriction injury model of neuropathic pain. Experimental Neurology 169: 386–391.
Wang, Y., A.M. Schmeichel, H. Iida, J.D. Schmelzer, and P.A. Low. 2006. Enhanced inflammatory response via activation of NF-kappaB in acute experimental diabetic neuropathy subjected to ischemia-reperfusion injury. Journal of Neurological Sciences 247: 47–52.
Srinivasan, S., and L. Pari. 2012. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chemico-Biological Interactions 195: 43–51.
Kastrup, J., P. Petersen, A. Dejgard, H.R. Angelo, and J. Hilsted. 1987. Intravenous lidocaine infusion—a new treatment of chronic painful diabetic neuropathy? Pain 28: 69–75.
Tanrikulu, Y., M. Sahin, K. Kismet, S.S. Kilicoglu, E. Devrim, et al. 2013. The protective effect of diosmin on hepatic ischemia reperfusion injury: an experimental study. Bosnian Journal of Basic Medical Sciences 13: 218–224.
Silambarasan, T., and B. Raja. 2012. Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats. European Journal of Pharmacology 679: 81–89.
Tahir, M., M.U. Rehman, A. Lateef, R. Khan, A.Q. Khan, et al. 2013. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-alpha and NF-kappaB activation. Alcohol 47: 131–139.
Tanrikulu, Y., K. Kismet, S. Serin Kilicoglu, E. Devrim, S. Erel, et al. 2011. Diosmin ameliorates intestinal injury induced by hepatic ischemia reperfusion in rats. Bratislavské Lekárske Listy 112: 545–551.
Golbabapour, S., M. Hajrezaie, P. Hassandarvish, N. Abdul Majid, A.H. Hadi, et al. 2013. Acute toxicity and gastroprotective role of M. pruriens in ethanol-induced gastric mucosal injuries in rats. BioMed Research International 2013: 974185.
Tahir, M., M.U. Rehman, A. Lateef, A.Q. Khan, R. Khan, et al. 2013. Diosmin abrogates chemically induced hepatocarcinogenesis via alleviation of oxidative stress, hyperproliferative and inflammatory markers in murine model. Toxicology Letters 220: 205–218.
Rehman, M.U., M. Tahir, A. Quaiyoom Khan, R. Khan, A. Lateef, et al. 2013. Diosmin protects against trichloroethylene-induced renal injury in Wistar rats: plausible role of p53, Bax and caspases. British Journal of Nutrition 110: 699–710.
Jain, D., M.K. Bansal, R. Dalvi, A. Upganlawar, and R. Somani. 2014. Protective effect of diosmin against diabetic neuropathy in experimental rats. Journal of Integrative Medicine 12: 35–41.
Nayak, S.S., and T.N. Pattabiraman. 1981. A new colorimetric method for the estimation of glycosylated hemoglobin. Clinica Chimica Acta 109: 267–274.
Lowry, O.H., N.J. Rosebrough, A.L. Farr, and R.J. Randall. 1951. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193: 265–275.
Wright, J.R., H.D. Colby, and P.R. Miles. 1981. Cytosolic factors which affect microsomal lipid peroxidation in lung and liver. Archives of Biochemistry and Biophysics 206: 296–304.
Jollow, D.J., J.R. Mitchell, N. Zampaglione, and J.R. Gillette. 1974. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11: 151–169.
Ezejiofor, A.N., C.N. Orish, and O.E. Orisakwe. 2014. Cytological and biochemical studies during the progression of alloxan-induced diabetes and possible protection of an aqueous leaf extract of Costus afer. Chinese Journal of Natural Medicines 12: 745–752.
Maiti, R., D. Jana, U.K. Das, and D. Ghosh. 2004. Antidiabetic effect of aqueous extract of seed of Tamarindus indica in streptozotocin-induced diabetic rats. Journal of Ethnopharmacology 92: 85–91.
Oloyede, H. O., Bello, T. O., Ajiboye, T. O., Salawu, M. O. 2015 Antidiabetic and antidyslipidemic activities of aqueous leaf extract of Dioscoreophyllum cumminsii (Stapf) Diels in alloxan-induced diabetic rats. Journal of Ethnopharmacology.
Joshi, D.V., R.R. Patil, and S.R. Naik. 2014. Hydroalcohol extract of Trigonella foenum-graecum seed attenuates markers of inflammation and oxidative stress while improving exocrine function in diabetic rats. Pharmaceutical Biology 53: 201–211.
Whiting, D.R., L. Guariguata, C. Weil, and J. Shaw. 2011. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice 94: 311–321.
Crespo, M.E., J. Galvez, T. Cruz, M.A. Ocete, and A. Zarzuelo. 1999. Anti-inflammatory activity of diosmin and hesperidin in rat colitis induced by TNBS. Planta Medica 65: 651–653.
Williams, R.J., J.P. Spencer, and C. Rice-Evans. 2004. Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine 36: 838–849.
Kanthlal, S.K., B.A. Kumar, J. Joseph, R. Aravind, and P.R. Frank. 2014. Amelioration of oxidative stress by Tabernamontana divaricata on alloxan-induced diabetic rats. Ancient Science of Life 33: 222–228.
Frode, T.S., and Y.S. Medeiros. 2008. Animal models to test drugs with potential antidiabetic activity. Journal of Ethnopharmacology 115: 173–183.
Pinto, I. F., Silva, R. P., Filho, A. B., Dantas, L. S., Bispo VS, et al. 2015. Study of antiglycation, hypoglycemic, and nephroprotective activities of the green dwarf variety coconut water (Cocos nucifera L.) in Alloxan-Induced Diabetic Rats. Journal of Medicinal Food.
Tashakori-Sabzevar, F., Ramezani, M., Hosseinzadeh, H., Parizadeh, S. M., Movassaghi, A. R., et al. 2016. Protective and hypoglycemic effects of celery seed on streptozotocin-induced diabetic rats: experimental and histopathological evaluation. Acta Diabetologica.
Palsamy, P., and S. Subramanian. 2008. Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomedicine and Pharmacotherapy 62: 598–605.
Pinto, I.F., R.P. Silva, B. Chaves Filho Ade, L.S. Dantas, V.S. Bispo, et al. 2015. Study of antiglycation, hypoglycemic, and nephroprotective activities of the green dwarf variety coconut water (Cocos nucifera L.) in alloxan-induced diabetic rats. Journal of Medicinal Food 18: 802–809.
Dabla, P.K. 2010. Renal function in diabetic nephropathy. World Journal of Diabetes 1: 48–56.
Palsamy, P., and S. Subramanian. 2011. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochimica et Biophysica Acta 1812: 719–731.
Wang, G.G., X.H. Lu, W. Li, X. Zhao, and C. Zhang. 2011. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evidence-based Complementary and Alternative Medicine 2011: 323171.
Cooper, M.E. 1998. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 352: 213–219.
Sheetz, M.J., and G.L. King. 2002. Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 288: 2579–2588.
Brownlee, M. 2001. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820.
Zou, C., Qiu, Q., Chen, H., Dou, L., Liang, J. 2015. Hepatoprotective effects of selenium during diabetes in rats. Human & Experimental Toxicology.
Pal, P.B., K. Sinha, and P.C. Sil. 2014. Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFalpha related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats. PLoS One 9, e107220.
Hensley, K., and R.A. Floyd. 2002. Reactive oxygen species and protein oxidation in aging: a look back, a look ahead. Archives of Biochemistry and Biophysics 397: 377–383.
Fang, J., T. Seki, and H. Maeda. 2009. Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Advanced Drug Delivery Reviews 61: 290–302.
Bondeva, T., and G. Wolf. 2014. Reactive oxygen species in diabetic nephropathy: friend or foe? Nephrology, Dialysis, Transplantation 29: 1998–2003.
Khan, S.R. 2013. Stress oxidative: nephrolithiasis and chronic kidney diseases. Minerva Medica 104: 23–30.
Prince, P.S., V.P. Menon, and L. Pari. 1998. Hypoglycaemic activity of Syzigium cumini seeds: effect on lipid peroxidation in alloxan diabetic rats. Journal of Ethnopharmacology 61: 1–7.
Kim, M.J., and Y. Lim. 2013. Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage. Mediators of Inflammation 2013: 510212.
Evans, J.L., I.D. Goldfine, B.A. Maddux, and G.M. Grodsky. 2002. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocrine Reviews 23: 599–622.
Yu, G., R. Wan, G. Yin, J. Xiong, Y. Hu, et al. 2014. Diosmetin ameliorates the severity of cerulein-induced acute pancreatitis in mice by inhibiting the activation of the nuclear factor-kappaB. International Journal of Clinical and Experimental Pathology 7: 2133–2142.
Kolati, S.R., E.R. Kasala, L.N. Bodduluru, J.R. Mahareddy, S.K. Uppulapu, et al. 2015. BAY 11–7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-kappaB pathway. Environmental Toxicology and Pharmacology 39: 690–699.
Karin, M. 1999. How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene 18: 6867–6874.
Liu, W., X. Zhang, P. Liu, X. Shen, T. Lan, et al. 2010. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. European Journal of Pharmacology 638: 150–155.
Ho, E., G. Chen, and T.M. Bray. 1999. Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice. FASEB Journal 13: 1845–1854.
DiDonato, J.A., M. Hayakawa, D.M. Rothwarf, E. Zandi, and M. Karin. 1997. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388: 548–554.
Mercurio, F., H. Zhu, B.W. Murray, A. Shevchenko, B.L. Bennett, et al. 1997. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278: 860–866.
Vallon, V. 2011. The proximal tubule in the pathophysiology of the diabetic kidney. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 300: R1009–R1022.
Imig, J.D., and M.J. Ryan. 2013. Immune and inflammatory role in renal disease. Comprehensive Physiology 3: 957–976.
Imam, F., N.O. Al-Harbi, M.M. Al-Harbi, M.A. Ansari, K.M. Zoheir, et al. 2015. Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-kappaB activation against LPS-induced acute lung injury in mice. Pharmacological Research 102: 1–11.
Navarro, J.F., and C. Mora-Fernandez. 2006. The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications. Cytokine and Growth Factor Reviews 17: 441–450.
Navarro, J. F., Milena, F. J., Mora, C., Leon, C., Claverie, F., et al. 2005. Tumor necrosis factor-alpha gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition. Kidney International Supplement: S98–102.
Duran-Salgado, M.B., and A.F. Rubio-Guerra. 2014. Diabetic nephropathy and inflammation. World Journal of Diabetes 5: 393–398.
Kiemer, A.K., T. Hartung, and A.M. Vollmar. 2000. cGMP-mediated inhibition of TNF-alpha production by the atrial natriuretic peptide in murine macrophages. Journal of Immunology 165: 175–181.
Yegin, S.C., F. Yur, S. Cetin, and A. Guder. 2015. Effect of lycopene on serum nitrite-nitrate levels in diabetic rats. Indian Journal of Pharmacuetical Sciences 77: 357–360.
Yao, Y., J. Yang, D. Wang, F. Zhou, X. Cai, et al. 2013. The aqueous extract of Lycopus lucidus Turcz ameliorates streptozotocin-induced diabetic renal damage via inhibiting TGF-beta1 signaling pathway. Phytomedicine 20: 1160–1167.
Pourghasem, M., E. Nasiri, and H. Shafi. 2014. Early renal histological changes in alloxan-induced diabetic rats. International Journal of Molecular and Cellular Medicine 3: 11–15.
Evan, A.P., S.A. Mong, B.A. Connors, G.R. Aronoff, and F.C. Luft. 1984. The effect of alloxan, and alloxan-induced diabetes on the kidney. Anatomical Record 208: 33–47.
Pourghasem, M., H. Shafi, and Z. Babazadeh. 2015. Histological changes of kidney in diabetic nephropathy. Caspian Journal of Internal Medicine 6: 120–127.
Acknowledgments
This research was supported by the National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, under the aegis of Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India. The authors acknowledge Institutional Biotech Hub (IBThub) NIPER-Guwahati, for providing necessary facilities and equipment’s to carry out this work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that there is no conflict of interests.
Rights and permissions
About this article
Cite this article
Ahmed, S., Mundhe, N., Borgohain, M. et al. Diosmin Modulates the NF-kB Signal Transduction Pathways and Downregulation of Various Oxidative Stress Markers in Alloxan-Induced Diabetic Nephropathy. Inflammation 39, 1783–1797 (2016). https://doi.org/10.1007/s10753-016-0413-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-016-0413-4