Hypertension and
sodium retention are features of a diminished
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). The activity of this
enzyme is reduced in various disease states with abnormal renal
sodium retention and
hypertension, including
preeclampsia.
ATP release to the extracellular compartment is observed with shear stress,
inflammation, and placental
ischemia. It was hypothesized that
ATP downregulates
11beta-HSD2 activity. For that purpose, cell lines from different tissues that previously were used to study the regulation of
11beta-HSD2 were investigated: JEG-3, a vascular trophoblastic; LLCPK1, a renal tubular; and SW620, a colonic epithelial cell line. The
11beta-HSD2 activity, assessed by the conversion of 3H-cortisol to
cortisone, was reversibly reduced during incubation with
ATP or its stable analogue
ATPgammaS in intact JEG-3 and LLCPK1, but not in SW620 cells. In JEG-3 cells, the purinergic antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic
acid but not
suramin reversed the inhibition. Incubation with
UTP and
ADP and their degradation products including
adenosine and
alpha,beta-methylene-ATP did not inhibit
11beta-HSD2 activity. In contrast,
11beta-HSD2 activity increased almost 2.5-fold after incubation with 2'-methylthio-ATP. This indicates a bidirectional regulation by
nucleotides via
purinergic receptors. In JEG-3 cells,
ATP/
ATPgammaS did not alter
11beta-HSD2 promoter activity but reduced
11beta-HSD2 protein and
mRNA concentration and half-life, suggesting a posttranscriptional regulation. In conclusion,
ATP inhibits cell type specifically via
purinergic receptors the expression and activity of the
11beta-HSD2 by a posttranscriptional mechanism.