title: Neuroprotection by rat Müller glia against high glucose-induced neurodegeneration through a mechanism involving ERK1/2 activation.
abstract: Müller cell activation is an early finding in diabetic retinopathy (DR), but its physiopathologic role in the disease is still unclear, especially in the early phases. We investigated on Müller glial activation in primary rat retinal cultures, exposed to High Glucose (HG), and in retinas from streptozotocin (stz)-induced diabetic rats. First of all, we checked if the presence of Müller glia influenced HG neurotoxicity. In mixed glial/neuronal retinal cultures, a single HG administration (sHG) for 48 h induced activation of Müller glia, in absence of neuronal damage. In contrast, in pure neuronal cultures, a marked neurotoxic effect was detected, suggesting that in this cell model Müller glia protect neurons from HG neurotoxicity. To better mimic the diabetic milieu, where retinal cells are constantly bathed in hyperglycemic fluid, and to further characterize astrocytic neuroprotective ability, mixed retinal cultures were exposed to repeated daily replacement of HG (rHG). In this paradigm, starting from 48 h, increased apoptosis and synaptic loss were observed, even in the presence of Müller cells. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whose activation triggers a prosurvival pathway, was increased by sHG, while it was down-regulated by rHG, suggesting that ERK1/2 activation is involved in neuroprotection. Consistently, in presence of ERK1/2 inhibitor PD98059, sHG exerted a proapoptotic effect also in glial/neuronal retinal cultures. In line with the in vitro data, early changes in diabetic retinas from stz-injected rats included Müller cell activation and increased pERK1/2 levels, but no signs of neuronal damage. These results suggest that, in the early phases of DR, Müller glial activation does not contribute to neurodegeneration, but may indeed have a neuroprotective activity against HG-induced neurotoxicity through a mechanism involving pERK1/2.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Matteucci
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gaddini
authors.affiliation: GB Bietti Eye Foundation IRCCS, Via Livenza, 3, 00198 Rome, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Villa
authors.affiliation: GB Bietti Eye Foundation IRCCS, Via Livenza, 3, 00198 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Varano
authors.affiliation: GB Bietti Eye Foundation IRCCS, Via Livenza, 3, 00198 Rome, Italy.
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Parravano
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Monteleone
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia 19129, PA, USA.
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Leo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Mallozzi
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. Electronic address: fiorella.malchiodialbedi@iss.it.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Malchiodi-Albedi
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pricci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000503:physiopathology*; D063928:Ependymoglial Cells / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects*
chemical_list: D005947:Glucose
keywords: Müller cells; apoptosis; diabetic retinopathy; extracellular signal-regulated kinase 1/2; high glucose; neurotoxicity; primary retinal cultures; streptozotocin