title: Enhanced survival of retinal ganglion cells is mediated by Müller glial cell-derived PEDF.
abstract: The death of retinal ganglion cells (RGC) leads to visual impairment and blindness in ocular neurodegenerative diseases, primarily in glaucoma and diabetic retinopathy; hence, mechanisms that contribute to protecting RGC from ischemia/hypoxia are of great interest. We here address the role of retinal glial (Müller) cells and of pigment-epithelium-derived factor (PEDF), one of the main neuroprotectants released from the glial cells. We show that the hypoxia-induced loss in the viability of cultured purified RGC is due to apoptosis, but that the number of viable RGC increases when co-cultured with Müller glial cells suggesting that glial soluble mediators attenuate the death of RGC. When PEDF was ablated from Müller cells a significantly lower number of RGC survived in RGC-Müller cell co-cultures indicating that PEDF is a major survival factor allowing RGC to escape cell death. We further found that RGC express a PEDF receptor known as patatin-like phospholipase domain-containing protein 2 (PNPLA2) and that PEDF exposure, as well as the presence of Müller cells, leads to an activation of nuclear factor (NF)-κB in RGC. Furthermore, adding an NF-κB inhibitor (SN50) to PEDF-treated RGC cultures reduced the survival of RGC. These findings strongly suggest that NF-κB activation in RGC is critically involved in the pro-survival action of Müller-cell derived PEDF and plays an important role in maintaining neuronal survival.
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany. Electronic address: jandarius.unterlauft@medizin.uni-leipzig.de.
authors.forename: Jan Darius
authors.initials: JD
authors.lastname: Unterlauft
authors.affiliation: ENSAIA, UR AFPA, Team BFLA, Université de Lorraine, Vandœuvre-lès-Nancy Cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Claudepierre
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Müller
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Yafai
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wiedemann
authors.affiliation: Paul Flechsig Institute for Brain Research, Pathophysiology of Glia, University of Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichenbach
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Eichler
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D063928:Ependymoglial Cells / Q000166:cytology* / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D010455:Peptides; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C118258:SN50 peptide
keywords: Müller cells; PEDF; hypoxia; neurodegeneration; retinal ganglion cells