title: An Essential Role of NRF2 in Diabetic Wound Healing.
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.
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Southern Arizona Limb Salvage Alliance, Department of Surgery, The University of Arizona, Tucson, AZ.
authors.forename: Manish
authors.initials: M
authors.lastname: Bharara
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Base for Drug Clinical Trial, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA.
authors.forename: Pak K
authors.initials: PK
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ dzhang@pharmacy.arizona.edu fnf7703@hotmail.com wondrak@pharmacy.arizona.edu.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.affiliation: 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.
authors.forename: Hongting
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ dzhang@pharmacy.arizona.edu fnf7703@hotmail.com wondrak@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D017719:Diabetic Foot / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D020780:Matrix Metalloproteinase 9