title: Aldosterone modulates endothelial permeability and endothelial nitric oxide synthase activity by rearrangement of the actin cytoskeleton.
abstract: Aldosterone (Aldo) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Aldo alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells were exposed to Aldo (10(-9) mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions and activation of intracellular signaling pathways were determined. Aldo increased endothelial permeability for molecules ≤ 70 kDa within 60 minutes. A transient loss of cortical actin with formation of actin stress fibers and disruption of continuous adherens and tight junction strands accompanied these changes. Mineralocorticoid receptor blockade, inhibition of RhoA, or disruption of extracellular-regulated protein kinase1/2 signaling pathways attenuated the Aldo-related effects. Moreover, Aldo-induced cytoskeletal rearrangement led to rapid dephosphorylation of protein kinase B and subsequent deactivation of endothelial nitric oxide synthase. Ex vivo tracer flux experiments with Evans blue-conjugated albumin demonstrated a concordant response to Aldo in freshly isolated umbilical arteries. Furthermore, low-dose cortisol (3 × 10(-10) to 3 × 10(-9) mol/L) mimics the effect of Aldo on endothelial integrity, and Aldo, by upregulating11β-hydroxysteroid dehydrogenase type 2, might even aggravate this deleterious effect of low-dose cortisol. We suggest that these mechanisms may contribute to the vasculopathy induced by inappropriate mineralocorticoid receptor activation.
authors.affiliation: Division of Nephrology, Hannover Medical School, Hannover, Germany. Kirsch.Torsten@MH-Hannover.de
authors.forename: Torsten
authors.initials: T
authors.lastname: Kirsch
authors.forename: Michaela
authors.initials: M
authors.lastname: Beese
authors.forename: Kristin
authors.initials: K
authors.lastname: Wyss
authors.forename: Uwe
authors.initials: U
authors.lastname: Klinge
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Marion
authors.initials: M
authors.lastname: Haubitz
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
mesh_terms: D000199:Actins / Q000378:metabolism*; D000450:Aldosterone / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D020742:rhoA GTP-Binding Protein; D006854:Hydrocortisone