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Human optic nerve head astrocytes as a target for endothelin-1
Ganesh Prasanna1, Raghu Krishnamoorthy, Abbot F Clark
1Department of Pharmacology and Neuroscience, Division of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Investigative Ophthalmology & Visual Science
|July 31, 2002
Summary
Endothelin-1 (ET-1) stimulates human optic nerve head astrocyte (hONA) proliferation via ET(A/B) receptor activation. This finding suggests ET-1 may contribute to optic nerve head changes in glaucoma.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Endothelin-1 (ET-1) levels are elevated in glaucomatous eyes.
- ET-1 administration in animal models causes glial activation and optic nerve damage, mimicking glaucoma.
- Optic nerve head astrocytes (hONAs) are implicated in glaucomatous changes.
Purpose of the Study:
- To investigate if human optic nerve head astrocytes (hONAs) are target cells for endothelin-1 (ET-1).
- To determine if ET-1 causes hONA proliferation, a process observed in glaucomatous optic nerve heads.
- To elucidate the specific ET-1 receptors involved in hONA proliferation.
Main Methods:
- Human optic nerve head astrocytes (hONAs) were treated with ET-1.
- Cell proliferation was assessed using formazan assays and [3H]thymidine uptake.
- ET receptor antagonists (BQ788, BQ610, PD142893) and an agonist (S6C) were used to determine receptor involvement.
- Intracellular calcium ([Ca2+]i) was measured using fura-2 imaging.
- RT-PCR was employed to detect mRNA expression for ET-1 and its receptors.
Main Results:
- ET-1 induced a time-dependent proliferation of hONAs, confirmed by two assays.
- Proliferation was blocked by a mixed ET(A/B) antagonist (PD142893).
- Effects were mediated through ET(B) receptor activation (blocked by ET(B) antagonist BQ788, mimicked by ET(B) agonist S6C) and ET(A) receptor involvement (blocked by ET(A) antagonist BQ610).
- ET-1 also increased intracellular calcium ([Ca2+]i) in hONAs.
- hONAs expressed mRNA for ET(A) and ET(B) receptors and preproET-1, suggesting autocrine/paracrine potential.
Conclusions:
- ET-1 stimulates astroglial proliferation in cultured human optic nerve head astrocytes (hONAs) via activation of both ET(A) and ET(B) receptors.
- This mechanism is comparable to ET-1-induced proliferation in brain astrocytes.
- Elevated ET-1 in glaucoma may contribute to hONA proliferation within the optic nerve head.