Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase.
11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. Recent work suggests that a nicotinamide adenine dinucleotide (NAD+)-dependent 11 beta-OHSD isoform is expressed in distal renal tubule, in contrast with the hepatic isoform which is NAD(+)-phosphate (NADP+)-dependent. To establish the distribution of the NAD(+)-dependent isoform we measured in vitro conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in homogenized rat tissues in the presence of NADP+ or NAD+. In most tissues (liver, testis, hippocampus, heart, aorta, mesenteric artery) NADP+ increased activity and NAD+ was without effect. However, in whole renal cortex, colon, placenta, and lung both NADP+ and NAD+ increased activity. No difference in cofactor utilization was demonstrated between proximal and distal renal tubules following density gradient separation. This distribution of NAD(+)-dependent activity corresponds with: (i) the distribution of multiple mRNA and/or protein species of 11 beta-OHSD; (ii) the distribution of aldosterone-specific mineralocorticoid receptors; and (iii) the equilibrium between active and inactive glucocorticoids in each tissue. We suggest that the tissue-specific expression of isoforms of 11 beta-OHSD with different kinetic properties confers on them diverse roles in modulating corticosteroid receptor activation.
Walker
B R
BR
University of Edinburgh, Department of Medicine, Western General Hospital, Scotland, UK.
Campbell
J C
JC
Williams
B C
BC
Edwards
C R
CR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D003106:Colon / Q000201:enzymology; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006913:Hydroxysteroid Dehydrogenases / Q000032:analysis* / Q000378:metabolism; D007672:Kidney Cortex / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D009243:NAD / Q000494:pharmacology*; D009249:NADP / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D009243:NAD; D009249:NADP; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C003552:11-dehydrocorticosterone; D003345:Corticosterone