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

Author:

Li Zhilian123,Li Yan234,Overstreet Jessica M.23,Chung Sungjin23,Niu Aolei23,Fan Xiaofeng23,Wang Suwan23,Wang Yinqiu23,Zhang Ming-Zhi23,Harris Raymond C.235ORCID

Affiliation:

1. Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong, China

2. Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN

3. Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN

4. Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

5. Department of Veterans Affairs, Nashville, TN

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.

Funder

National Institues of Health, National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Veterans Affairs

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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