Changes in neuronal response to ischemia in retinas with genetic alterations of somatostatin receptor expression.
Ischemia is a primary cause of neuronal death in retinal diseases. The repertoire of expressed transmitter receptors would determine the neurons' responses to ischemic damage, and peptidergic receptors may be involved. With a new in vitro model of the ischemic mouse retina, we investigated whether an altered expression of somatostatin receptors could modulate retinal responses to ischemia. We used retinas of somatostatin receptor 1 (sst(1)) knock out (KO) mice, where sst(2) are over-expressed and over-functional, and of sst(2) KO mice. TUNEL analysis of ischemic retinas showed a marked reduction of cell death in sst(1) KO retinas, while there were no differences between wild-type (WT) and sst(2) KO retinas. In addition, caspase-3 mRNA expression was also reduced in sst(1) KO as compared to WT retinas. An immunohistochemical analysis demonstrated that different cell populations responded differently to the ischemic insult, and that the persistence of some immunohistochemical markers was greater in sst(1) KO than in WT or in sst(2) KO retinas. In particular, rod bipolar cell survival was markedly improved in sst(1) KO retinas, while it was dramatically decreased in sst(2) KO retinas. Furthermore, consistent with a role of glutamate excitotoxicity in ischemia-induced neuronal death, retinal glutamate release was observed to increase under ischemic conditions, but this increase was significantly reduced in sst(1) KO retinas. These observations demonstrate that an increased presence of functional sst(2) protects against retinal ischemia, thus implementing the background for the use of sst(2) analogs in therapies of retinal diseases such as glaucoma or diabetic retinopathy.
Catalani
Elisabetta
E
Dipartimento di Scienze Ambientali, Università della Tuscia, Largo dell'Università snc, Blocco D, 01100 Viterbo, Italy.
Cervia
Davide
D
Martini
Davide
D
Bagnoli
Paola
P
Simonetti
Elisa
E
Timperio
Anna Maria
AM
Casini
Giovanni
G
D000818:Animals; D019393:Arrestin / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019393:Arrestin; D050485:GABA Plasma Membrane Transport Proteins; D007211:Indoles; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; C007293:DAPI; C093733:somatostatin receptor 2; D014446:Tyrosine 3-Monooxygenase; D053148:Caspase 3