Role of the ETB receptor in retinal ganglion cell death in glaucoma.
Recent observations suggest that the vasoactive peptide endothelin-1 (ET-1) may be an important contributor to the etiology of glaucoma. ET-1 administration has been shown to produce optic nerve axonal loss and apoptosis of retinal ganglion cells. Ocular ET-1 levels are elevated in aqueous humor in response to elevated intraocular pressure both in glaucoma patients and in animal models of glaucoma; however, the precise mechanisms by which ET-1 mediates glaucomatous optic neuropathy are not clear. Presently we report that ET-1-mediated apoptosis was markedly attenuated in ETB receptor-deficient rats, suggesting a key role for ETB receptors in apoptosis of retinal ganglion cells by ET-1 treatment. Using virally transformed rat retinal ganglion cells (RGC-5 cells), we found that ET-1 (100 nmol/L) treatment produced apoptotic changes in these cells that was determined by flow cytometric analyses, release of mitochondrial cytochrome c to the cytosol, and increased phosphorylation of c-Jun N-terminal kinase. Pretreatment with the ETB-receptor antagonist BQ788 (1 micromol/L) was able to significantly attenuate ET-1-mediated apoptosis in RGC-5 cells. ET-1-mediated apoptotic changes in RGC-5 cells were associated with ETB-receptor activation and were accompanied by a significant upregulation of ETB-receptor expression. These studies suggest that ocular ET-1 acts through ETB receptors to mediate apoptosis of retinal ganglion cells, a key event in glaucoma and related optic neuropathies.
Department of Pharmacology and Neuroscience, UNT Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. rkrishna@hsc.unt.edu
Raghu R
RR
Krishnamoorthy
Vidhya R
VR
Rao
Rachel
R
Dauphin
Ganesh
G
Prasanna
Christina
C
Johnson
Thomas
T
Yorio
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002461:Cell Line, Transformed; D017931:DNA Primers / Q000235:genetics; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology; D005901:Glaucoma / Q000209:etiology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D051381:Rats; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D017931:DNA Primers; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases