title: Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFα related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats.
abstract: Oxidative stress plays a crucial role in the progression of diabetic nephropathy in hyperglycemic conditions. It has already been reported that mangiferin, a natural C-glucosyl xanthone and polyhydroxy polyphenol compound protects kidneys from diabetic nephropathy. However, little is known about the mechanism of its beneficial action in this pathophysiology. The present study, therefore, examines the detailed mechanism of the beneficial action of mangiferin on STZ-induced diabetic nephropathy in Wister rats as the working model. A significant increase in plasma glucose level, kidney to body weight ratio, glomerular hypertrophy and hydropic changes as well as enhanced nephrotoxicity related markers (BUN, plasma creatinine, uric acid and urinary albumin) were observed in the experimental animals. Furthermore, increased oxidative stress related parameters, increased ROS production and decreased the intracellular antioxidant defenses were detected in the kidney. Studies on the oxidative stress mediated signaling cascades in diabetic nephropathy demonstrated that PKC isoforms (PKCα, PKCβ and PKCε), MAPKs (p38, JNK and ERK1/2), transcription factor (NF-κB) and TGF-β1 pathways were involved in this pathophysiology. Besides, TNFα was released in this hyperglycemic condition, which in turn activated caspase 8, cleaved Bid to tBid and finally the mitochorndia-dependent apoptotic pathway. In addition, oxidative stress also disturbed the proapoptotic-antiapoptotic (Bax and Bcl-2) balance and activated mitochorndia-dependent apoptosis via caspase 9, caspase 3 and PARP cleavage. Mangiferin treatment, post to hyperglycemia, successfully inhibited all of these changes and protected the cells from apoptotic death.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Pabitra Bikash
authors.initials: PB
authors.lastname: Pal
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Sinha
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Parames C
authors.initials: PC
authors.lastname: Sil
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D006943:Hyperglycemia / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C013592:mangiferin; D013311:Streptozocin; D014969:Xanthine Oxidase; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D006909:Hydroxyproline