Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling.
Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Here, we show that endothelin-1 (ET-1) dose-dependently inhibits the hypoosmotic swelling of Müller cells in freshly isolated retinal slices of control and diabetic rats, with a maximal inhibition at 100 nM. Osmotic Müller cell swelling was also inhibited by ET-2. The effect of ET-1 was mediated by activation of ETAand ETBreceptors resulting in transactivation of metabotropic glutamate receptors, purinergic P2Y1, and adenosine A1receptors. ET-1 (but not ET-2) also inhibited the osmotic swelling of bipolar cells in retinal slices, but failed to inhibit the swelling of freshly isolated bipolar cells. The inhibitory effect of ET-1 on the bipolar cell swelling in retinal slices was abrogated by inhibitors of the FGF receptor kinase (PD173074) and of TGF-β1 superfamily activin receptor-like kinase receptors (SB431542), respectively. Both Müller and bipolar cells displayed immunoreactivities of ETAand ETBreceptor proteins. The data may suggest that neuroprotective effects of ETs in the retina are in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. ET-1 acts directly on Müller cells, while the inhibitory effect of ET-1 on bipolar cell swelling is indirectly mediated, via stimulation of the release of growth factors like bFGF and TGF-β1 from Müller cells.
Paul Flechsig Institute of Brain Research, University of Leipzig, 04103, Leipzig, Germany.|Department of Ophthalmology, Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany.
Stefanie
S
Vogler
Institute of Human Genetics, University of Regensburg, 93053, Regensburg, Germany.
Antje
A
Grosche
Paul Flechsig Institute of Brain Research, University of Leipzig, 04103, Leipzig, Germany.
Thomas
T
Pannicke
Department of Ophthalmology, Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany.
Peter
P
Wiedemann
Paul Flechsig Institute of Brain Research, University of Leipzig, 04103, Leipzig, Germany.
Andreas
A
Reichenbach
Department of Ophthalmology, Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany. bria@medizin.uni-leipzig.de.
Andreas
A
Bringmann
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D016232:Endothelins / Q000494:pharmacology*; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009995:Osmosis / Q000187:drug effects*; D009997:Osmotic Pressure / Q000187:drug effects; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D016232:Endothelins; D036341:Intercellular Signaling Peptides and Proteins
Bipolar cell; Cell swelling; Diabetic retinopathy; Endothelin; Müller cell; Retina