Sharma Kamalesh K, Lindqvist Annika, Zhou Xin J, Auchus Richard J, Penning Trevor M, Andersson Stefan
Department of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell Endocrinol. 2006 Mar 27;248(1-2):79-86. doi: 10.1016/j.mce.2005.10.024. Epub 2005 Dec 5.
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, 11beta-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 17alpha- and 11beta-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 AKR1C3 protects the mineralocorticoid receptor from activation by DOC in mineralocorticoid target cells of the kidney and colon, analogous to cortisol inactivation by 11beta-hydroxysteroid dehydrogenase type 2.
醛固酮是人体内主要的内源性盐皮质激素，可调节盐和水平衡。皮质醇作为主要的糖皮质激素，对盐皮质激素受体具有高亲和力；然而，2型11β-羟基类固醇脱氢酶可将皮质醇在肾脏的醛固酮靶细胞中转化为无活性的类固醇可的松，从而限制了皮质醇的盐皮质激素作用。脱氧皮质酮（DOC）以高亲和力与盐皮质激素受体结合，其循环浓度与醛固酮相当。在17α-羟化酶和11β-羟化酶缺乏症中所见的严重DOC过量会导致高血压，而妊娠晚期中度DOC过量与高血压有关。在此，我们证明DOC可被人类AKR1C3同工酶的20-酮类固醇还原酶活性灭活。免疫组织化学分析表明，AKR1C3在肾皮质和髓质集合管以及结肠的盐皮质激素反应性上皮细胞中表达。我们的研究结果表明，AKR1C3可保护盐皮质激素受体免受肾脏和结肠盐皮质激素靶细胞中DOC的激活，类似于2型11β-羟基类固醇脱氢酶对皮质醇的灭活作用。
