Regulation of 11 beta-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol.
The 11beta-hydroxysteroid dehydrogenase (11betaHSD) type 1 (11betaHSD1) enzyme is an NADP+-dependent oxidoreductase, usually reductase, of major glucocorticoids. The NAD+-dependent type 2 (11betaHSD2) enzyme is an oxidase that inactivates cortisol and corticosterone, conferring extrinsic specificity of the mineralocorticoid receptor for aldosterone. We reported that addition of a reducing agent to renal homogenates results in the monomerization of 11betaHSD2 dimers and a significant increase in NAD+-dependent corticosterone conversion. Estrogenic effects on expression, dimerization, and activity of the kidney 11betaHSD1 and -2 enzymes are described herein. Renal 11betaHSD1 mRNA and protein expressions were decreased to very low levels by estradiol (E2) treatment of both intact and castrated male rats; testosterone had no effect. NADP+-dependent enzymatic activity of renal homogenates from E2-treated rats measured under nonreducing conditions was less than that of homogenates from intact animals. Addition of 10 mM DTT to aliquots from these same homogenates abrogated the difference in NADP+-dependent activity between E2-treated and control rats. In contrast, 11betaHSD2 mRNA and protein expressions were significantly increased by E2 treatment. There was a marked increase in the number of juxtamedullary proximal tubules stained by the antibody against 11betaHSD2 after the administration of E2. Notwithstanding, neither the total corticosterone and 11-dehydrocorticosterone excreted in the urine nor their ratio differed between E2- and vehicle-treated rats. NAD+-dependent enzymatic activity in the absence or presence of a reducing agent demonstrated that the increase in 11betaHSD2 protein was not associated with an increase in in vitro activity unless the dimers were reduced to monomers.
Gomez-Sanchez
Elise P
EP
Endocrine Section and Research Service, G. V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS 39216, USA. egomez-sanchez@medicine.umsmed.edu
Ganjam
Venkataseshu
V
Chen
Yuan Jian
YJ
Liu
Ying
Y
Zhou
Ming Yi
MY
Toroslu
Cigdem
C
Romero
Damian G
DG
Hughson
Michael D
MD
de Rodriguez
Angela
A
Gomez-Sanchez
Celso E
CE
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000818:Animals; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000652:urine; D019281:Dimerization; D004229:Dithiothreitol / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006913:Hydroxysteroid Dehydrogenases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology; D009249:NADP / Q000494:pharmacology; D009919:Orchiectomy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology
D012333:RNA, Messenger; D013739:Testosterone; D004958:Estradiol; D009249:NADP; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C003552:11-dehydrocorticosterone; D004229:Dithiothreitol; D003345:Corticosterone