title: Soluble adenylyl cyclase in vascular endothelium: gene expression control of epithelial sodium channel-α, Na+/K+-ATPase-α/β, and mineralocorticoid receptor.
abstract: The Ca(2+)- and bicarbonate-activated soluble adenylyl cyclase (sAC) has been identified recently as an important mediator of aldosterone signaling in the kidney. Nuclear sAC has been reported to stimulate cAMP response element-binding protein 1 phosphorylation via protein kinase A, suggesting an alternative cAMP pathway in the nucleus. In this study, we analyzed the sAC as a potential modulator of endothelial stiffness in the vascular endothelium. We determined the contribution of sAC to cAMP response element-mediated transcriptional activation in vascular endothelial cells and kidney collecting duct cells. Inhibition of sAC by the specific inhibitor KH7 significantly reduced cAMP response element-mediated promoter activity and affected cAMP response element-binding protein 1 phosphorylation. Furthermore, KH7 and anti-sAC small interfering RNA significantly decreased mRNA and protein levels of epithelial sodium channel-α and Na(+)/K(+)-ATPase-α. Using atomic force microscopy, a nano-technique that measures stiffness and deformability of living cells, we detected significant endothelial cell softening after sAC inhibition. Our results suggest that the sAC is a regulator of gene expression involved in aldosterone signaling and an important regulator of endothelial stiffness. Additional studies are warranted to investigate the protective action of sAC inhibitors in humans for potential clinical use.
authors.affiliation: University Hospital Muenster, Internal Medicine D, Department of Nephrology, Hypertension, and Rheumatology, Albert-Schweitzer-Campus 1, D-48149 Muenster, Germany. Eva.Brand@ukmuenster.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmitz
authors.forename: Johanna
authors.initials: J
authors.lastname: Nedele
authors.forename: Katrin
authors.initials: K
authors.lastname: Guske
authors.forename: Martina
authors.initials: M
authors.lastname: Maase
authors.forename: Malte
authors.initials: M
authors.lastname: Lenders
authors.forename: Michael
authors.initials: M
authors.lastname: Schelleckes
authors.forename: Kristina
authors.initials: K
authors.lastname: Kusche-Vihrog
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000502:physiology; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D059289:Vascular Stiffness / Q000502:physiology*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D053503:Epithelial Sodium Channels; D034741:RNA, Small Interfering; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D050882:CREB-Binding Protein; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase
keywords: adenylyl cyclase; aldosterone; cyclic AMP response element–binding protein; vascular stiffness