Role of endothelinergic receptors in retinal neuroinflammation

IRIBARNE M; TORBIDONI V; SUBURO AM

Nashville, TN

Simposio; Neuroprotective strategies in Degenerative Eye Disease; 2006

Department of Ophthalmology and Visual Sciences

Endothelin-1 (ET-1), which controls the permeability of blood-brain barrier, is released during sepsis. In previous studies, we described an increase in permeability of the inner vascular plexus of retinas under sepsis that could be significantly reduced by treatment with Tezosentan, a mixed antagonist of endothelinergic receptors ET-A and ET-B. Our present aims were to evaluate the association of endothelinergic receptors with the activation of stress markers.  Endotoxemia was induced by LPS injection (ip, 5mg/kg) in BALB-c mice. Two doses of Tezosentan (sc, 10mg/kg) were given: 1 hour before and 24 hours after LPS. Controls received saline at the same times. Animals were euthanized and fixed 1 hour after the last injection. Retinal sections were labeled with antibodies against ET-A, ET-B, the MAPK-related markers (Phospho-JNK, Phospho-p38), and Protein Kinase C (PKC). Under basal conditions, ET-B was present in astrocytes whereas ET-A was located in outer plexiform layer (OPL), amacrine and ganglion cell layer (GCL). LPS induced a large increase in these immunoreactivities, but Tezosentan treatment reduced that increase. Untreated animals showed Phospho-JNK immunoreactivity in inner plexiform layer (IPL), amacrine cells and axons of GCL, but exhibited Phospho-p38 in GCL cell bodies. Bipolar neurons and dendrites of GCL were PKC immunoreactive. LPS treatment increased Phospho-JNK and PKC immunoreactivities but did not modify Phospho-p38. Tezosentan treatment reduced Phospho-JNK but increased PKC.  Our observations indicate that endotoxemia would simultaneously upregulate expression of endothelinergic receptors and various stress markers. Behavior of immunoreactivities of stress markers after treatment with Tezosentan further suggests that blockade of endothelinergic receptors would differentially regulate various signaling pathways involved in stress and cell survival. Therefore, treatment with endothelinergic antagonists might provide protection against neuroinflammatory damage.