Epithelial Barrier Regulation by Hypoxia-Inducible Factor

Abstract

Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po₂ determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.

Keywords: cell–cell junction; creatine; creatine kinase; inflammation; metabolism.

Figure 1.

Epithelial junctional defects in cells lacking hypoxia-inducible factor (HIF) expression. (A) The localization of the adherens junction protein E-cadherin (E-cad) and the tight junction (TJ) protein zonula occludens (ZO)-1 in epithelial cells deficient in HIF-2α. Cells were depleted of HIF-2α by transduction of lentiviral short hairpin RNA. Shown here is a nontargeting control (shControl) and shHIF-2α. Note defective expression of both E-cad and ZO-1 in shHIF-2α cells. (B) Defective expression of the TJ proteins occludin and ZO-1 in cells lacking the HIF-1 and HIF-2 dimeric partner, HIF-1β. Adapted from References and . sh = short hairpin.