Fluid Shear Stress Reduces 11β-Hydroxysteroid Dehydrogenase Type 2

Abstract

Abstract-In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11␤-hydroxysteroid dehydrogenases (11␤-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11␤-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11␤-HSD1; however, 11␤-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11␤-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11␤-HSD2 activity yet did not prevent the ss response. The ss response was completely protein kinase C independent. The mitogen-activated protein kinase kinase inhibitor PD-098059 enhanced 11␤-HSD2 activity in static conditions yet only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (FA)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphorylation of FA kinase dose-dependently, thus maintaining 11␤-HSD2 activity. The 11␤-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11␤-HSD2 activity. In conclusion, JEG-3 cells express 11␤-HSD2, which is downregulated by ss. Regulatory mechanisms involve transcriptional control and require intact FA-cytoskeleton signaling and phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response. (Hypertension. 2001;37:160-169.)

Extracellular ATP Determines 11β-Hydroxysteroid Dehydrogenase Type 2 Activity via Purinergic Receptors

“…In JEG-3 cell homogenates, 11␤-HSD2 enzyme activity, assessed by the conversion of 3 H-cortisol to 3 H-cortisone, was present (1.46 Ϯ 0.15 pmol/mg protein per h) as has been shown previously (9,10,31). This conversion was almost completely inhibited when glycyrrhetinic acid (10 Ϫ6 mol/L) was added to the cell culture medium.…”

“…The cortisol/cortisone conversion was used to measure oxidation at C-11 by 11␤-HSD2 following protocols described earlier (9,10 …”

“…Placental ischemia and inflammatory responses during preeclampsia and increased shear stress lead to the release of ATP (9,(25)(26)(27). The cortisol-inactivating enzyme 11␤-HSD2 is highly expressed in trophoblasts and the trophoblast cell line JEG-3 (9,10,22). One important function of the 11␤-HSD2 in placental tissue is to protect the fetus from high maternal cortisol concentrations.…”

Impaired 11β‐hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis

“…Similarly, the downregulation of 11␤-HSD2 by shear stress, a characteristic of extreme renal vasoconstriction which requires focal adhesion-cytoskeleton interactions, was established in vitro in human cells exhibiting endothelial features. 48 On the other hand, the downregulation of 11␤-HSD2 by hypoxia has been observed in cell culture experiments, ischemic rat kidneys, and humans exposed to hypoxemia at high altitude and is mediated by a MAPK-dependent induction of Egr-1. 25,49,50 A peculiar feature of cirrhosis, with and without spontaneous bacterial peritonitis, is an inflammatory state that accounts at least in part for systemic hemodynamic derangements, including renal failure.…”

“…32 Pharmacological interventions with beta-blocking agents reduce release of renin, and angiotensin-converting enzyme inhibitors or ATII receptor blocking drugs alleviate ATII-mediated and possibly shear stress-mediated downregulation of 11␤-HSD2. 24,48,66 Whether converting enzyme inhibitors and ATII receptor blockers are useful xenobiotics in some patients with cirrhosis is an unresolved issue. Prevention or aggressive treatment of infection complications, a major cause of the development of hepatorenal syndrome, allows reduction of the release of TNF-␣ or nitric oxide and possibly hypoxemia, 3 mechanisms known to impair 11␤-HSD2 activity.…”