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First published on October 11, 2006; DOI: 10.1124/mol.106.029579

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Received for publication August 8, 2006.
Revised September 14, 2006.
Accepted for publication October 11, 2006.

Cellular Retinoic Acid Bioavailability Determines Epithelial Integrity: Role of Retinoic Acid Receptor Alpha Agonists in Colitis

Makoto Osanai 1*, Nami Nishikiori 1, Masaki Murata 1, Hideki Chiba 1, Takashi Kojima 1, Norimasa Sawada 1

1 Sapporo Medical University School of Medicine

* Address correspondence to: E-mail: osanaim{at}sapmed.ac.jp

Abstract

The epithelial barrier is primarily determined by intercellular tight junctions (TJs). We have previously demonstrated that all-trans retinoic acid (atRA) plays an important role in forming functional TJs through a specific retinoic acid receptor (RAR)/retinoid-X-receptor (RXR) heterodimer in epithelial cells. However, the physiological relevance of RAs in maintaining the epithelial integrity remains to be examined. Here we show that several types of RA, including atRA, promote the barrier function of epithelial TJs. Conversely, RA depletion in the cells by overexpressing CYP26s, cytochrome P450 enzymes specifically involved in the metabolic inactivation of RAs, induces an increase of permeability as measured by two differently sized tracer molecules, inulin and mannitol. This RA-mediated enhancement of barrier function is potentially associated with the increased expression of TJ-associated genes such as occludin, claudin-1, claudin-4, and ZO-1. We also found that RAR{alpha} is a preferential regulator of the epithelial barrier in vitro. Studies of murine experimental colitis, which is characterized by increased gut permeability, reveal that RAR{alpha} stimulation significantly attenuates the loss of the epithelial barrier during colitis in vivo. Our results suggest that cellular RA bioavailability determines the epithelial integrity, as it is a critical regulator for barrier protection during mucosal injuries.


Key words: Cytochrome P450, Oxidative stress, Pharmacokinetics, metabolism and activation


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