The role of NF-kappaB signaling in impaired liver tissue repair in thioacetamide-treated type 1 diabetic rats.
Previously we reported that an ordinarily nonlethal dose of thioacetamide (300 mg/kg) causes liver failure and 90% mortality in type 1 diabetic rats, primarily because of inhibited tissue repair. On the other hand, the diabetic rats receiving 30 mg thioacetamide/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic rats receiving 300 mg thioacetamide/kg, resulting in a delay in recovery from that liver injury and survival. These data indicate that impaired tissue repair in diabetes is a dose-dependent function of diabetes. The objective of the present study was to test the hypothesis that disrupted nuclear factor-kappaB (NF-kappaB)-regulated cyclin D1 signaling may explain dose-dependent impaired tissue repair in the thioacetamide-treated diabetic rats. Administration of 300 mg thioacetamide/kg to nondiabetic rats led to sustained NF-kappaB-regulated cyclin D1 signaling, explaining prompt compensatory tissue repair and survival. For the first time, we report that NF-kappaB-DNA binding is dependent on the dose of thioacetamide in the liver tissue of the diabetic rats. Administration of 300 mg thioacetamide/kg to diabetic rats inhibited NF-kappaB-regulated cyclin D1 signaling, explaining inhibited tissue repair, liver failure and death, whereas remarkably higher NF-kappaB-DNA binding but transient down regulation of cyclin D1 expression explains delayed tissue repair in the diabetic rats receiving 30 mg thioacetamide/kg. These data suggest that dose-dependent NF-kappaB-regulated cyclin D1 signaling explains inhibited versus delayed tissue repair observed in the diabetic rats receiving 300 and 30 mg thioacetamide/kg, respectively.
Devi
Sachin S
SS
Department of Toxicology, College of Pharmacy, The University of Louisiana, Monroe, LA 71209-0470, USA.
Mehendale
Harihara M
HM
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D013853:Thioacetamide / Q000633:toxicity*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D013311:Streptozocin; D004247:DNA; D000410:Alanine Transaminase; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases