Abstract

In diabetic retinopathy, the exact mechanisms leading to retinal capillary closure and to retinal barriers breakdown remain imperfectly understood. Rho-associated kinase (ROCK), an effector of the small GTPase Rho, involved in cytoskeleton dynamic regulation and cell polarity is activated by hyperglycemia. In one year-old Goto Kakizaki (GK) type 2 diabetic rats retina, ROCK-1 activation was assessed by its cellular distribution and by phosphorylation of its substrates, MYPT1 and MLC. In both GK rat and in human type 2 diabetic retinas, ROCK-1 is activated and associated with non-apoptotic membrane blebbing in retinal vessels and in retinal pigment epithelium (RPE) that respectively form the inner and the outer barriers. Activation of ROCK-1 induces focal vascular constrictions, endoluminal blebbing and subsequent retinal hypoxia. In RPE cells, actin cytoskeleton remodeling and membrane blebs in RPE cells contributes to outer barrier breakdown. Intraocular injection of fasudil, significantly reduces both retinal hypoxia and RPE barrier breakdown. Diabetes-induced cell blebbing may contribute to ischemic maculopathy and represent an intervention target.

Details

Title
ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy
Author
Rothschild, Pierre-Raphaël 1 ; Sawsen Salah 1   VIAFID ORCID Logo  ; Berdugo, Marianne 1 ; Gélizé, Emmanuelle 1 ; Delaunay, Kimberley 1 ; Naud, Marie-Christine 1 ; Klein, Christophe 1 ; Moulin, Alexandre 2 ; Savoldelli, Michèle 1 ; Bergin, Ciara 2 ; Jean-Claude Jeanny 1 ; Jonet, Laurent 1 ; Arsenijevic, Yvan 2 ; Behar-Cohen, Francine 3 ; Crisanti, Patricia 1 

1  Inserm UMR_S 1138, Team 17: From physiopathology of retinal diseases to clinical advances, Centre de Recherche des Cordeliers, Paris, France; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France 
2  Department of Ophthalmology of University of Lausanne 1000 Lausanne, Jules Gonin Hospital, Lausanne, Switzerland 
3  Inserm UMR_S 1138, Team 17: From physiopathology of retinal diseases to clinical advances, Centre de Recherche des Cordeliers, Paris, France; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Department of Ophthalmology, Assistance Publique-Hopitaux de Paris, Hôtel-Dieu de Paris Hospital, Paris, France; INSERM U1138 Team 17, Le Centre de Recherches des Cordeliers (CRC), Paris, France; University of Lausanne, Lausanne, Switzerland 
Pages
1-15
Publication year
2017
Publication date
Aug 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-07329-y
ProQuest document ID
1957252009
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.