Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes

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 with endothelial nitric oxide knockout [eNOS]). eNOS 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 () and transforming growth factor-α () 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 and 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.

Enhancer-Gene Interaction Analyses Identified the Epidermal Growth Factor Receptor as a Susceptibility Gene for Type 2 Diabetes Mellitus

“…A previous study revealed that inhibition of EGFR tyrosine kinase activity amelio- Diabetes Metab J 2020 Forthcoming. Posted online 2020 https://e-dmj.org rated insulin resistance [41]. In the present study, differential expression analyses using four GEO datasets confirmed that EGFR may be a novel gene for the risk of T2DM.…”

Eye, hepatobiliary, and renal disorders of erlotinib in patients with non-small-cell lung cancer: A meta-analysis

“…This may be explained that TKIs indirectly improves insulin sensitivity by inhibiting EGFR. Furthermore, one recent study has indicated that inhibition of EGFR by erlotinib is associated with improved diabetic nephropathy and insulin resistance in animal model with type 2 diabetes [87]. The above results are also associated with the low risk of renal disorder in the present meta-analysis.…”

Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis

“…CDDP: cisplatin; GL: Ganoderma lucidum; EOD: every other day; EGFR: epidermal growth factor receptor. 9 Oxidative Medicine and Cellular Longevity potential for AKI during endotoxemia and diabetic nephropathy [74,75]. Our results showed that the upregulation of EGFR, following CDDP injection, was significantly downregulated in rats treated with GL, and this correction was associated with the improvement that occurred in nephrotoxicity indices.…”