Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway.
OBJECTIVE
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.


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-beta1), p65 subunit of NFkappabeta and caspase-3.


RESULTS
After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate and active p65 subunit of NFkappabeta 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.


CONCLUSIONS
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.
Kuhad
Anurag
A
Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160 014, India.
Chopra
Kanwaljit
K
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D024508:Tocotrienols / Q000627:therapeutic use*
D000975:Antioxidants; D016328:NF-kappa B; D024508:Tocotrienols