Neuropeptide Y-evoked proliferation of retinal glial (Muller) cells.
BACKGROUND
Glial cells in human retinas and in fibrocellular membranes from patients with proliferative vitreoretinopathy (PVR) have been described to upregulate their expression of Y1 receptors for neuropeptide Y (NPY) (Soler et al.: Glia 39:320, 2002). However, it is unknown whether Y1 receptor activation causes proliferation of retinal glial cells. We investigated whether NPY exerts a proliferation-stimulating effect on retinal glial cells, and compared the NPY-evoked signaling with the signaling of purinergic P2Y receptors.


METHODS
Proliferation assays using bromodeoxyuridine were carried out on primarily cultured Muller glial cells of the guinea pig, in the absence and presence of blockers of Y1 receptors, of receptor tyrosine kinases (RTKs), of mitogen-activated protein kinases (MAPKs) and of phosphatidylinositol-3 kinase (PI3K).


RESULTS
NPY exerted a biphasic effect on Muller cell proliferation. At low concentrations (0.1 ng/ml and 1 ng/ml) it decreased the proliferation rate of the cells, while at higher concentration (100 ng/ml) it increased Muller cell proliferation. The NPY-evoked proliferation was mediated by Y1 receptor stimulation and by activation of the p44/p42 MAPKs and partially of the p38 MAPK. Moreover, Y1 receptor-induced activation of PI3K as well as transactivations of the platelet-derived and the epidermal growth factor RTKs were necessary for full mitogenic effect of NPY. Y1 and P2Y receptors share partially common signal transduction pathways in Muller cells.


CONCLUSIONS
It is suggested that NPY may be involved in stimulation of retinal glial cell proliferation during PVR when it is released at higher amounts into the injured retina.
Paul Flechsig Institute of Brain Research, University of Leipzig, Jahnallee 59, 04109, Leipzig, Germany.
Ivan
I
Milenkovic
Michael
M
Weick
Peter
P
Wiedemann
Andreas
A
Reichenbach
Andreas
A
Bringmann
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006168:Guinea Pigs; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology*; D009478:Neuropeptide Y / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D018048:Receptors, Purinergic P2; C097212:neuropeptide Y-Y1 receptor; D000255:Adenosine Triphosphate; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases