Protection of glucotoxicity by a tripeptide derivative of α‐melanocyte‐stimulating hormone in human epidermal keratinocytes. (3rd December 2018)

• Record Type: Journal Article
• Authors: Gkogkolou, P.; Sarna, M.; Sarna, T.; Paus, R.; Luger, T.A.; Böhm, M.
• Is Part Of: British journal of dermatology. Volume 180:Number 4(2019)
• Page Start: 836
• Page End: 848
• Publication Date: 2018-12-03
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.17125
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Chronic skin ulcers are a major complication and a therapeutic challenge in patients with diabetes mellitus. Glucose‐induced accumulation of reactive oxygen species (ROS) is considered to be an important pathogenetic factor in diabetes. Objectives: To characterize the impact of high glucose (HG) on normal human keratinocytes (NHKs) and examine if Lys‐d ‐Pro‐Thr (KdPT), a tripeptide derived from α‐melanocyte‐stimulating‐hormone, has protective effects. Methods: We investigated the key functions of NHKs under HG conditions with or without KdPT in vitro as well as ex vivo employing a skin organ culture model. Results: HG impaired metabolic activity, cell proliferation, viability and migration of NHKs. As shown by atomic force microscopy HG altered the biophysical properties of NHKs, i.e. cell size and elasticity. Glucotoxicity in NHKs was paralleled by the induction of intracellular ROS and endoplasmic reticulum stress. KdPT attenuated HG‐induced oxidative stress and antagonized the effects of glucose on cell viability, metabolic activity and migration. Importantly, KdPT also antagonized the suppressive effect of HG on epidermal migration in wounded human skin organ cultures. Conclusions: Our findings highlight a novel effect of KdPT that could be exploited for the future therapy of diabetic skin ulcers. Abstract : What's already known about this topic? Chronic skin ulcers are a major therapeutic challenge in patients with diabetes mellitus. Impairment of keratinocyte function is considered to be a key factor in impaired wound healing in patients with diabetes mellitus. Oxidative stress is increased in patients with diabetes mellitus. What does this study add? Insight into the precise impact of hyperglycaemic stress on cell viability, proliferation, migration, apoptosis, autophagy, oxidative and endoplasmic stress as well as on biomechanical properties of epidermal keratinocytes. Demonstration that a skin organ culture model can be used to examine the effect of hyperglycaemic stress ex vivo . Analysis of the effects of a small melanocortin‐derived peptide, Lys‐d ‐Pro‐Thr (KdPT), on glucotoxicity of epidermal keratinocytes in vitro and in a skin organ culture model. What is the translational message? Better understanding of the pathobiology of glucotoxicity on epidermal keratinocytes. Demonstration that KdPT may be a drug candidate for preclinical studies on diabetic wound healing. Respond to this article Plain language summary available online