Role of the ETB receptor in retinal ganglion cell death in glaucoma

Raghu R. Krishnamoorthy, Vidhya R. Rao, Rachel Dauphin, Ganesh Prasanna, Christina Johnson, Thomas Yorio

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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 μmol/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.

Original languageEnglish
Pages (from-to)380-393
Number of pages14
JournalCanadian Journal of Physiology and Pharmacology
Volume86
Issue number6
DOIs
StatePublished - Jun 2008

Keywords

  • Apoptosis
  • Endothelin receptor B
  • Endothelin-1
  • Neuroprotection
  • Optic neuropathy
  • Retinal ganglion cells (RGCs)

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