Distribution of glucocorticoid and mineralocorticoid receptors and 11beta-hydroxysteroid dehydrogenases in human and rat ocular tissues.
OBJECTIVE
The administration of glucocorticoids as topical or systemic medications may lead to the development of ocular hypertension through the induction of morphologic and biochemical changes in the trabecular meshwork leading to a reduction in the facility of aqueous outflow. Glucocorticoids exert their physiological effects by binding to and activating glucocorticoid and mineralocorticoid receptors. The activity of glucocorticoids is critically regulated at a prereceptor level by the two isozymes of 11beta-hydroxysteroid dehydrogenase. The purpose of this study was to determine the distribution of glucocorticoid target receptors and the isozymes of 11beta-hydroxysteroid dehydrogenase (11 beta-HSD) that regulate the activity of glucocorticoids at a prereceptor level in human and rat ocular tissues.


METHODS
Horizontal sections of normal adult human and rat eyes were cut and hybridized with 35S-labeled cRNA probes specific for the glucocorticoid receptor, mineralocorticoid receptor, and 11beta-HSD types 1 and 2 using in situ hybridization. Immunohistochemical analysis of glucocorticoid and mineralocorticoid receptors using monoclonal antibodies was carried out on rat eye tissue sections. Whole rat eyes were homogenized and the activity of 11beta-HSD types 1 and 2 in the eye assessed as the percentage conversion of tritiated corticosterone to tritiated 11-dehydrocortico-sterone when corticosterone was added to the homogenate.


RESULTS
In the rat ocular tissues mRNAs encoding glucocorticoid receptor, mineralocorticoid receptor, and 11beta-HSD types 1 and 2 were detected in nonpigmented ciliary epithelium, trabecular meshwork, corneal epithelium and endothelium, and anterior lens epithelium. Immunohistochemistry confirmed the presence of glucocorticoid and mineralocorticoid receptors at these sites. Activity of both isozymes of 11beta-HSD was demonstrated in homogenized rat eyes (percentage conversion of tritiated corticosterone to 11-dehydrocorticosterone; mean +/- SD, 11beta-HSD 1 = 15% +/- 5.3%, 11beta-HSD 2 = 7.9% +/- 2.8%). In both human and rat eyes, expression of mRNAs encoding glucocorticoid receptor and 11beta-HSD type 1 was high in the trabecular meshwork and lens epithelium, whereas expression of mRNAs encoding the mineralocorticoid receptor and 11beta-HSD type 2 was high in nonpigmented ciliary epithelium and corneal epithelium and endothelium.


CONCLUSIONS
Glucocorticoid target receptors and the enzymes regulating glucocorticoid activity at these receptors are present in mammalian ocular tissues, which regulate aqueous humor formation and outflow. Alteration in the number or affinity of receptors or in the activity of regulatory enzymes may alter the susceptibility of certain individuals to the effects of glucocorticoids on intraocular pressure.
Stokes
J
J
Department of Medicine, University of Edinburgh, Western General Hospital, Scotland. jstokes@srv0.med.ed.ac.uk
Noble
J
J
Brett
L
L
Phillips
C
C
Seckl
J R
JR
O'Brien
C
C
Andrew
R
R
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D000869:Anterior Eye Segment / Q000378:metabolism*; D000911:Antibodies, Monoclonal; D002924:Ciliary Body / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D015347:RNA Probes; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D007527:Isoenzymes; D015347:RNA Probes; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases