An essential role of NRF2 in diabetic wound healing

Min Long, Montserrat Rojo De La Vega, Qing Wen, Manish Bharara, Tao Jiang, Rui Zhang, Shiwen Zhou, Pak Kin Wong, Georg T Wondrak, Hongting Zheng, Donna Zhang

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

The high mortality and disability of diabetic nonhealing skin ulcers create an urgent need for the development of more efficacious strategies targeting diabetic wound healing. In the current study, using human clinical specimens, we show that perilesional skin tissues from patients with diabetes are under more severe oxidative stress and display higher activation of the nuclear factor-E2-related factor 2 (NRF2)-mediated antioxidant response than perilesional skin tissues from normoglycemic patients. In a streptozotocin-induced diabetes mouse model, Nrf2-/- mice have delayed wound closure rates compared with Nrf2+/+ mice, which is, at least partially, due to greater oxidative DNA damage, low transforming growth factor-β1 (TGF-β1) and high matrix metalloproteinase 9 (MMP9) expression, and increased apoptosis. More importantly, pharmacological activation of the NRF2 pathway significantly improves diabetic wound healing. In vitro experiments in human immortalized keratinocyte cells confirm that NRF2 contributes to wound healing by alleviating oxidative stress, increasing proliferation and migration, decreasing apoptosis, and increasing the expression of TGF-β1 and lowering MMP9 under high-glucose conditions. This study indicates an essential role for NRF2 in diabetic wound healing and the therapeutic benefits of activating NRF2 in this disease, laying the foundation for future clinical trials using NRF2 activators in treating diabetic skin ulcers.

Original languageEnglish (US)
Pages (from-to)780-793
Number of pages14
JournalDiabetes
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Long, M., De La Vega, M. R., Wen, Q., Bharara, M., Jiang, T., Zhang, R., Zhou, S., Wong, P. K., Wondrak, G. T., Zheng, H., & Zhang, D. (2016). An essential role of NRF2 in diabetic wound healing. Diabetes, 65(3), 780-793. https://doi.org/10.2337/db15-0564