title: Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27 dependent actin cytoskeletal organization.
abstract: Cilia are mechanosensing organelles that communicate extracellular signals into intracellular responses. Altered functions of primary cilia play a key role in the development of various diseases including polycystic kidney disease. Here, we show that endothelial cells from the oak ridge polycystic kidney (Tg737(orpk/orpk) ) mouse, with impaired cilia assembly, exhibit a reduction in the actin stress fibers and focal adhesions compared to wild-type (WT). In contrast, endothelial cells from polycystin-1 deficient mice (pkd1(null/null) ), with impaired cilia function, display robust stress fibers, and focal adhesion assembly. We found that the Tg737(orpk/orpk) cells exhibit impaired directional migration and endothelial cell monolayer permeability compared to the WT and pkd1(null/null) cells. Finally, we found that the expression of heat shock protein 27 (hsp27) and the phosphorylation of focal adhesion kinase (FAK) are downregulated in the Tg737(orpk/orpk) cells and overexpression of hsp27 restored both FAK phosphorylation and cell migration. Taken together, these results demonstrate that disruption of the primary cilia structure or function compromises the endothelium through the suppression of hsp27 dependent actin organization and focal adhesion formation, which may contribute to the vascular dysfunction in ciliopathies.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio 44272, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jones
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Adapala
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Chris
authors.initials: C
authors.lastname: Bursley
authors.forename: Wissam A
authors.initials: WA
authors.lastname: AbouAlaiwi
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D002923:Cilia / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D007690:Polycystic Kidney Diseases / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D055551:HSP27 Heat-Shock Proteins