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Diabetes. 2016 Mar;65(3):780-93. doi: 10.2337/db15-0564. Epub 2015 Dec 30.

An Essential Role of NRF2 in Diabetic Wound Healing.

Author information

1
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China Base for Drug Clinical Trial, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
2
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
3
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ Department of Pharmacy, Jinan Central Hospital, Shandong University, Shandong, People's Republic of China.
4
Southern Arizona Limb Salvage Alliance, Department of Surgery, The University of Arizona, Tucson, AZ.
5
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
6
Base for Drug Clinical Trial, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
7
Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA.
8
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ dzhang@pharmacy.arizona.edu fnf7703@hotmail.com wondrak@pharmacy.arizona.edu.
9
Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China dzhang@pharmacy.arizona.edu fnf7703@hotmail.com wondrak@pharmacy.arizona.edu.

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.

PMID:
26718502
PMCID:
PMC4764153
[Available on 2017-03-01]
DOI:
10.2337/db15-0564
[Indexed for MEDLINE]
Free PMC Article

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