TY - JOUR
T1 - An essential role of NRF2 in diabetic wound healing
AU - Long, Min
AU - De La Vega, Montserrat Rojo
AU - Wen, Qing
AU - Bharara, Manish
AU - Jiang, Tao
AU - Zhang, Rui
AU - Zhou, Shiwen
AU - Wong, Pak K.
AU - Wondrak, Georg T.
AU - Zheng, Hongting
AU - Zhang, Donna D.
N1 - Funding Information:
Funding. This work was supported by the State Scholarship Fund of China (201207610022 to M.L.), the Chongqing Science Foundation (cstc2013jcsfC10001-5 to M.L.), the National Cancer Institute (R21CA166926 to G.T.W. and D.D.Z.; R01 CA154377 to D.D.Z.), the National Natural Science Foundation of China (81228023 to H.Z. and D.D.Z.; 81471039 to H.Z.), and the National Institute of Environmental Health Sciences (R01 ES015010 to D.D.Z. and ES006694 [a center grant]).
Publisher Copyright:
© 2016 by the American Diabetes Association.
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
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U2 - 10.2337/db15-0564
DO - 10.2337/db15-0564
M3 - Article
C2 - 26718502
AN - SCOPUS:84962343940
SN - 0012-1797
VL - 65
SP - 780
EP - 793
JO - Diabetes
JF - Diabetes
IS - 3
ER -