Renal Dysfunction Aggravated Impaired Diabetic Cutaneous Wound Healing
ping xie, Mimi wu young, Huining Bian, Solmaz N. Leilabadi, Seok Hong, Thomas A. Mustoe, Robert D. Galiano.
northwestern university, Chicago, IL, USA.
Background: Renal dysfunction has been associated with an increased incidence of foot ulcers as well as worsened outcomes of wound healing in the diabetic population. The purpose of this study was to create an excisional wound healing model in diabetic mice with renal dysfunction to investigate the combined effects of diabetes and nephropathy on cutaneous ulcers. Methods: Renal impairment was introduced in diabetic db/db mice through unilateral nephrectomy and electro-coagulation of the contralateral kidney. Renal function was subsequently monitored with blood urea nitrogen (BUN) assays throughout the study. After 8 weeks, splinted, full thickness excisional wounds were created on the dorsal skin, and harvested on postoperative days (POD) 7 and 14 for further measurement of wound healing parameters including proliferation, angiogenesis, inflammation , reactive oxygen species, and apoptosis through histology, immunostaining and quantitative PCR (qPCR). Results: Renal injury promoted the increase of BUN in three weeks after initial operation, and maintained at a doubled level compared to control throughout the entirety of the study. Diabetic mice with renal injury displayed notably impaired wound healing processes represented by decreased re-epithelialization (Keratin 14) and granulation tissue deposition, concurrent with significant reductions in cellular proliferation (Ki67) and angiogenesis (CD31), as well as significant increases in inflammatory response (M1 macrophages), oxidative stress (nitro-tyrosine) and cellular apoptosis. Furthermore, qPCR results also displayed corresponding changes of related genes (TNF-α, IL-1β, SOD2) in the wounds of renal injured db/db mice. Conclusions: Renal manipulation through unilateral nephrectomy with electro-coagulation of the contralateral kidney accelerated the progress of renal impairment, which was demonstrated to aggravate impaired cutaneous wound healing in diabetic mice.
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