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Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.
- Source :
- Diabetes; Sep2018, Vol. 67 Issue 9, p1847-1857, 11p
- Publication Year :
- 2018
-
Abstract
- 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 db/db with endothelial nitric oxide knockout [eNOS-/-db/db]). eNOS-/-db/db mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity (waved 2) and transforming growth factor-α (waved 1) were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both waved 1 and waved 2 diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity. [ABSTRACT FROM AUTHOR]
- Subjects :
- DIABETES
CARBOHYDRATE intolerance
ENDOCRINE diseases
NUTRITION disorders
INSULIN resistance
DRUG resistance
EPIDERMAL growth factor receptors
HYPOGLYCEMIC agents
MEMBRANE proteins
TYPE 2 diabetes complications
PROTEIN kinase inhibitors
ALBUMINURIA
ANIMAL experimentation
CYTOKINES
DIABETIC nephropathies
EPIDERMAL growth factor
GENETIC techniques
GLOMERULONEPHRITIS
GROWTH factors
KIDNEYS
MACROPHAGES
MICE
TYPE 2 diabetes
OXIDOREDUCTASES
T cells
OXIDATIVE stress
FIBROSIS
CHEMICAL inhibitors
PREVENTION
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 67
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 131346726
- Full Text :
- https://doi.org/10.2337/db17-1513