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Pathophysiology

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

  1. Zhilian Li1,2,3,
  2. Yan Li2,3,4,
  3. Jessica M. Overstreet2,3,
  4. Sungjin Chung2,3,
  5. Aolei Niu2,3,
  6. Xiaofeng Fan2,3,
  7. Suwan Wang2,3,
  8. Yinqiu Wang2,3,
  9. Ming-Zhi Zhang2,3⇑ and
  10. Raymond C. Harris2,3,5⇑
  1. 1Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong, China
  2. 2Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
  3. 3Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN
  4. 4Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  5. 5Department of Veterans Affairs, Nashville, TN
  1. Corresponding author: Raymond C. Harris, ray.harris{at}vanderbilt.edu, or Ming-Zhi Zhang, ming-zhi.zhang{at}vanderbilt.edu.
  1. Z.L. and Y.L. contributed equally to this work.

Diabetes 2018 Sep; 67(9): 1847-1857. https://doi.org/10.2337/db17-1513
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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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1513/-/DC1.

  • Received December 14, 2017.
  • Accepted June 18, 2018.
  • © 2018 by the American Diabetes Association.
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Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes
Zhilian Li, Yan Li, Jessica M. Overstreet, Sungjin Chung, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yinqiu Wang, Ming-Zhi Zhang, Raymond C. Harris
Diabetes Sep 2018, 67 (9) 1847-1857; DOI: 10.2337/db17-1513

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Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes
Zhilian Li, Yan Li, Jessica M. Overstreet, Sungjin Chung, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yinqiu Wang, Ming-Zhi Zhang, Raymond C. Harris
Diabetes Sep 2018, 67 (9) 1847-1857; DOI: 10.2337/db17-1513
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