title: Tumor necrosis factor alpha pathways develops liver apoptosis in type 1 diabetes mellitus.
abstract: We analyzed the contribution of TNF-α intracellular pathway in the development of apoptosis in the liver of streptozotocin-induced diabetic rats. In liver tissue, diabetes promoted a significant increase of TNF-α/TNF-R1, and led to the activation of caspase-8, of nuclear factor kappa B (NFκB), and JNK signaling pathways. The activation of NFκB led to an induction of iNOS and consequent increase in NO production. As a consequence of such changes a significant increase of caspase-3 activity and of apoptotic index were observed in the liver of diabetic animals. Importantly, the treatment in vivo of diabetic rats with etanercept (TNF-α blocking antibody) or aminoguanidine (selective iNOS inhibitor) significantly attenuated the induction of apoptosis by reduction of caspase-3 activity. Overall, we demonstrated that in the diabetes enhances TNF-α in the liver, which may be a fundamental key leading to apoptotic cell death, through activation of caspase-8, NFκB and JNK pathways.
authors.affiliation: Institute of Experimental Physiology (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina.
authors.forename: Paola I
authors.initials: PI
authors.lastname: Ingaramo
authors.forename: María T
authors.initials: MT
authors.lastname: Ronco
authors.forename: Daniel E A
authors.initials: DE
authors.lastname: Francés
authors.forename: Juan A
authors.initials: JA
authors.lastname: Monti
authors.forename: Gerardo B
authors.initials: GB
authors.lastname: Pisani
authors.forename: María P
authors.initials: MP
authors.lastname: Ceballos
authors.forename: Mónica
authors.initials: M
authors.lastname: Galleano
authors.forename: María C
authors.initials: MC
authors.lastname: Carrillo
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Carnovale
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D004578:Electron Spin Resonance Spectroscopy; D000068800:Etanercept; D006146:Guanidines / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D061945:Caspase Inhibitors; D006146:Guanidines; D007074:Immunoglobulin G; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D000068800:Etanercept; C004479:pimagedine