Attenuation of diabetic nephropathy by tocotrienol: Involvement of NFkB signaling pathway

Aim: Diabetic nephropathy is a serious complication for patients with diabetes mellitus. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end stage renal disease. The study was designed to evaluate the impact of tocotrienol on renal function and reno-inflammatory cascade in streptozotocin-induced diabetes. Main methods: Streptozotocin (STZ)-induced diabetic rats were treated with tocotrienol (25,50 and 100 mg/kg), alpha-tocopherol (100 mg/kg) or with vehicle form 5th to 8th weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney was prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, non protein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1beta (TGF-beta 1), p65 subunit of NF kappa beta and caspase-3. Key findings: After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta 1, caspase-3 activity in cytoplasmic lysate and active p65 subunit of NF kappa beta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of tocotrienol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Tocotrienol (100 mg/kg) was demonstrated to be more effective than alpha-tocopherol (100 mg/kg). Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced effect on molecular parameters as compared to their respective groups. Significance: Taken together, the data reveal that tocotrienol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation and apoptosis and thus exerts a marked renoprotective effect. (C) 2009 Elsevier Inc. All rights reserved.