Early effects of high glucose in retinal tissue cultures Renin-Angiotensin system-dependent and -independent signaling.
The early effects of the diabetic milieu on retinal tissue and their relation to the Renin-Angiotensin system (RAS) activation are poorly known. Here we investigated RAS signaling in retinas explanted from adult rats exposed for 48 h to high glucose (HG), with or without the Angiotensin Converting Enzyme inhibitor enalaprilat, which blocks RAS. HG was observed to i) initiate a phosphotyrosine-dependent signaling cascade; ii) up-regulate Angiotensin(1) Receptor (AT(1)R); iii) activate src tyrosine kinase and increase phosphorylation of Pyk2, PLCgamma1 and ERK1/2; and iv) activate Akt and the transcription factor CREB. In the presence of enalaprilat, tyrosine phosphorylation signal and AT(1)R upregulation decreased and activation of PLCgamma1 and CREB reverted, showing their relation to RAS signaling. In line with Akt activation, no apoptosis or synapse degeneration was found. Müller glia was activated, but in a RAS-independent manner. Our results suggest that, in early phases of HG exposure, a pro-survival cell program may be induced in the retina.
Gaddini
Lucia
L
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
Villa
Marika
M
Matteucci
Andrea
A
Mallozzi
Cinzia
C
Petrucci
Tamara C
TC
Di Stasi
Anna Maria M
AM
Leo
Lanfranco
L
Malchiodi-Albedi
Fiorella
F
Pricci
Flavia
F
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015773:Enalaprilat / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D012160:Retina / Q000187:drug effects / Q000502:physiology*; D055351:Retinal Neurons / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D044140:Receptor, Angiotensin, Type 1; D019000:Phosphotyrosine; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma; D015773:Enalaprilat; D005947:Glucose