Raymond Harris, MD, and colleagues previously showed that the epidermal growth factor receptor (EGFR) is activated in mouse models of type 1 diabetes and that drugs which inhibit EGFR prevent the development of DN.
EGFR becomes active when phosphate molecules attach at specific tyrosine sites in the protein. The phosphorylated tyrosines become the docking sites for a variety of molecules that regulate cell proliferation, maturation, and cell death.
In this study, they 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.
Now in a study published in the journal Diabetes, Harris, Ming-Zhi Zhang, MD, and colleagues show that blocking EGFR tyrosine kinase activity with the drug erlotinib but also improved weight gain and reduced insulin resistance in mice.
Their work suggests that pathways activated by EGFR may be attractive targets to treat DN. For his discovery of EGF, Vanderbilt's Stanley Cohen, Ph.D., shared the Nobel Prize in medicine in 1986.