Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:248

Article; Proceedings Paper

Sharma, KK ; Lindqvist, A ; Zhou, XJ ; Auchus, RJ ; Penning, TM ; Andersson, S

关键词: DOC;    mineralocorticoid;    inactivation;    AKR1C3;    human;    kidney;    colon;   

DOI  :  10.1016/j.mce.2005.10.024

来源: Elsevier

【 摘 要 】

Aldosterone is the principal endogenous mineralocorticoid in humans and regulates salt and water homeostasis. Cortisol, the major glucocorticoid, has high affinity for the mineralocorticoid receptor; however, 11 beta-hydroxysteroid dehydrogenase type 2 converts cortisol to the inactive steroid cortisone in aldosterone target cells of the kidney, thus limiting the mineralocorticoid action of cortisol. Deoxycorticosterone (DOC) binds to the mineralocorticocoid receptor with high affinity and circulates at concentrations comparable to aldosterone. Severe DOC excess as is seen in 17 alpha-and 11 beta-hydroxylase deficiencies causes hypertension, and moderate DOC overproduction in late pregnancy is associated with hypertension. Here, we demonstrate that DOC is inactivated by the 20-ketosteroid reductase activity of the human AKR1C3 isozyme. Immunohistochemical analyses demonstrate that AKR1C3 is expressed in the mineralocorticoid-responsive epithelial cells of the renal cortical and medullary collecting ducts, as well as the colon. Our findings suggest that AKRIC3 protects the mineralocorticoid receptor from activation by DOC in mineralocorticoid target cells of the kidney and colon, analogous to cortisol inactivation by 11 beta-hydroxysteroid dehydrogenase type 2. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

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