Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues.
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.
Sharma
Kamalesh K
KK
Department of Obstetrics-Gynecology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lindqvist
Annika
A
Zhou
Xin J
XJ
Auchus
Richard J
RJ
Penning
Trevor M
TM
Andersson
Stefan
S
D015096:3-Hydroxysteroid Dehydrogenases / Q000032:analysis / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000201:enzymology*; D003900:Desoxycorticosterone / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000032:analysis / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D008901:Mineralocorticoids / Q000378:metabolism / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism
D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; D013256:Steroids; D003900:Desoxycorticosterone; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3