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Nrf2 Deficiency Delays Diabetic Wound Healing
Trevor Ellison, BS1, Utkarsh Anil, BA2, Jonathan Massie, BS3, Sophia Hameedi, BS2, Bukhtawar Waqas, BS2, Adis Bajraktarevic, BS2, Sainithin Kuntamukkala, BS2, Piul Rabbani, PhD2, Daniel Ceradini, MD2.
1Carnegie Mellon University, Pittsburgh, PA, USA, 2New York University, New York, NY, USA, 3Michigan State University, East Lansing, MI, USA.

Purpose: Redox homeostasis management is critical in cutaneous wound healing, especially in a diabetic environment. We found that upregulating Nrf2-mediated antioxidants in diabetic wounds promotes re-epithelialization with well-vascularized granulation tissue. We aimed to elucidate whether Nrf2 signaling in the epidermis and vasculature are impaired in diabetic skin.
Methods: 5µm tissue sections from 10mm-diameter excisional humanized cutaneous wounds on WT, diabetic, and Nrf2-/- mice were stained for K14, K10, CD31, Nrf2 using immunofluorescence to visualize spatial expression.
Results: Nrf2 is highly expressed in basal-K14+-epidermis, K10+ cells and CD31+ endothelial cells in WT skin. Nrf2 is upregulated in epidermis, dermis and granulation tissue by 7 days post-wounding with gradient expression longitudinally with higher signal nearby wound bed. Nrf2 shows gradient expression in dermis, lower signal in deep dermis. Nrf2 is downregulated in intact diabetic skin epidermis, dermis, and fails to upregulate post-wounding. Compared to WT, Nrf2-/- wounds generate 17% less granulation tissue(223500 units2 vs 305900 unit2), have 29% lower concentration of CD31+ cells(3.0 vs 4.3 cells/hpf) in granulation tissue at 7 days post-wounding, and demonstrate 24% longer time to closure(17.3 days vs 14.0 days), p<0.05.
Conclusions: Nrf2 expression is highly expressed in tissues that are known to cope with high levels of ROS. Similarities between Nrf2-/- and diabetic skin wounds suggest that decreased Nrf2 expression is a driving factor for poor diabetic wound healing because of poor ROS management in epidermis, granulation tissue and endothelial cells. Our results validate the targeting of Nrf2/Keap1 pathway to develop effective therapies for diabetic wounds.


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