REGULATORY HIF CASCADE IN EPIDERMAL KERATINOCYTES: DYNAMICS OF ACTIVITY AND DEPENDENCE ON HYPOXIA

DOI: https://doi.org/None

A.A. Panteleyev (1), L.A. Usakin (1), E.V. Solovieva (1), M.A. Paltsev (2) 1 -National Research Centre «Kurchatov Institute», Akademika Kurchatova pl., 1, Moscow, 123182, Russian Federation; 2 -N. M. Emanuel Institute of Biochemical Physics, Kosygina str., 4, Moscow, 119334, Russian Federation

Introduction. The transcriptional activity of hypoxia-inducible factor 1 (HIF1) not only drives cellular adaptation to O2 deficiency, but also plays an important role in the development and functioning of various organs and tissues. Data on the role of HIF regulatory pathway (and of hypoxia in general) in control of skin functions remain be fragmented and ambiguous. The aim. of the study was to elucidate the dynamics of HIF1activity in the epidermis, its dependence on hypoxia and its role in controlling the differentiation of epidermal keratinocytes in vitro and in vivo. Methods. As experimental models we have used transgenic mice with a modified activity of HIF1 in the epidermis, as well as cultures of human (N-TERT) and mouse epidermal keratinocytes. As experimental tools real time PCR, Western blotting and immunohistochemistry have been used. Results. The experiments in vitro showed that both human and mouse keratinocytes respond to acute hypoxia (1% O2) with HIF1α stabilization and transactivation of the classical HIF1 target genes – placental growth factor (PlGF) and vascular endothelial growth factor A (VEGFA). At the same time, hypoxia had a negative effect upon HIF1α mRNA level. Experiments in mice with abolished epidermal Arnt gene (and correspondingly, suppression of HIF1 activity) showed that HIF1 controls the expression of epidermal filament aggregating protein (filaggrin, FLG) and loricrin (LOR) – the proteins that play a pivotal role in keratinocyte differentiation and formation of epidermal barrier. Conclusion. Studies in vitro and in vivo showed that hypoxia activates in epidermal keratinocytes classical HIF1 cascade, which activates not only known HIF1-dependent genes (VEGFα, PLGF), but also the expression of specific epidermal proteins Flg and Lor, controlling keratinocyte differentiation and epidermal barrier function. These findings point to the potential applicability of modulating HIF1 activity in the epidermis as a therapeutic tool in treatment of skin keratinization disorders
Keywords: 
hypoxia, HIF cascade, epidermal differentiation, keratinocytes
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