transforming-growth-factor-alpha and Diabetes-Mellitus--Type-2

Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS

Topics: Albuminuria; Animals; Biomarkers; Crosses, Genetic; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; ErbB Receptors; Erlotinib Hydrochloride; Fibrosis; Glomerulonephritis; Hypoglycemic Agents; Insulin Resistance; Kidney; Macrophages; Membrane Transport Modulators; Mice, Knockout; Mice, Mutant Strains; Nitric Oxide Synthase Type III; Oxidative Stress; Protein Kinase Inhibitors; T-Lymphocytes; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Blood Pressure; Cells, Cultured; Dependovirus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; ErbB Receptors; Extracellular Matrix; Female; Gene Transfer Techniques; Genetic Vectors; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Mice, 129 Strain; Mice, Knockout; Middle Aged; Nephrectomy; Phosphorylation; Renin-Angiotensin System; Signal Transduction; Time Factors; Transforming Growth Factor alpha

Topics: Chromosomes, Human, Pair 2; Diabetes Mellitus, Type 2; DNA Primers; Gene Library; Hearing Loss, Sensorineural; Humans; Kidney Diseases; Obesity; Retinitis Pigmentosa; Syndrome; Transforming Growth Factor alpha

We have previously demonstrated in short-term experiments that altered hepatocytes in liver acini draining the blood from intraportally transplanted pancreatic islets in streptozotocin-induced diabetic rats with mild persisting diabetes resemble those in preneoplastic foci of altered hepatocytes. We now present the results of long-term studies (up to 22 months) in this animal model. Glycogen-storing foci (which were the first parenchymal alteration observed some days after transplantation) persisted at least for 6 months, when the first mixed-cell foci and the first hepatocellular adenoma emerged. After 15 to 22 months, 86% of the animals exhibited at least one hepatocellular adenoma and four animals (19%) showed a hepatocellular carcinoma. The transplants were found in a close spatial relationship with the preneoplastic foci and the hepatocellular neoplasms. The mitotic indices, the 5-bromo-2'-desoxyuridine labeling indices and the apoptotic indices showed significant differences between the unaltered liver parenchyma, different types of preneoplastic foci, and hepatocellular neoplasms. The immunohistochemical expression of transforming growth factor-alpha increased during the stepwise development from glycogen-storing liver acini to hepatocellular carcinomas. Hepatocarcinogenesis in this new animal model is probably due to the hormonal and growth-stimulating effects of insulin secreted by the intraportally transplanted islets of Langerhans in diabetic rats.

Topics: Adenoma; Animals; Blood Glucose; Body Weight; Carcinoma, Hepatocellular; Case-Control Studies; Cause of Death; Cytoplasm; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Immunohistochemistry; Islets of Langerhans Transplantation; Liver Neoplasms, Experimental; Male; Microscopy, Electron; Neoplasm Staging; Precancerous Conditions; Rats; Rats, Inbred Lew; Streptozocin; Transforming Growth Factor alpha

The genetically diabetic db/db mouse is an excellent model to study the effect of diabetes on hormone receptors. The decrease of EGF binding sites could be detected in the hepatic microsomes of diabetic mice as early as 3 weeks of age. In addition, there was an age-related decrease in the autophosphorylating activity of EGF receptor isolated from the liver of diabetic mice. Estrone feeding (0.005%) partially restored this autophosphorylating activity. Northern blot analysis showed that the hepatic EGF receptor transcripts were dramatically decreased during the progression of diabetes and could be reversed by estrone feeding. Transfection experiments carried out on HepG2 cells using EGF receptor promoter (pERCAT-6) demonstrated that addition of 2 x 10(-8) M estrone stimulated chloramphenicol acetyltransferase activity. Our results suggest that estrone modulates EGF receptor by enhancing EGF receptor transcripts and the promoter activity of this gene.

Topics: Animals; Chloramphenicol O-Acetyltransferase; Diabetes Mellitus, Type 2; Epidermal Growth Factor; ErbB Receptors; Estrone; Female; Liver; Mice; Mice, Inbred C57BL; Phosphorylation; RNA, Messenger; Transforming Growth Factor alpha