Abstract:
PURPOSE:Glaucoma is a distinct neuropathy characterized by the chronic and progressive death of retinal ganglion cells (RGCs). The etiology of RGC death remains unknown. Risk factors for glaucomatous RGC death are elevated intraocular pressure and glial production of tumor necrosis factor-alpha (TNF-α). Previously, the authors showed that glaucoma causes a rapid upregulation of a neurotrophin receptor truncated isoform lacking the kinase domain, TrkC.T1, in retina. Here they examined the biological role of TrkC.T1 during glaucoma progression. METHODS:Rat and mouse models of chronic ocular hypertension were used. Immunofluorescence Western blot analysis and in situ mRNA hybridization were used to identify cells upregulating TrkC.T1. A genetic model of engineered mice lacking TrkC.T1 (TrkC.T1(-/-)) was used to validate a role for this receptor in glaucoma. Pharmacologic studies were conducted to evaluate intravitreal delivery of agonists or antagonists of TrkC.T1, compared with controls, during glaucoma. Surviving RGCs were quantified by retrograde-labeling techniques. Production of neurotoxic TNF-α and α2 macroglobulin were quantified. RESULTS:TrkC.T1 was upregulated in retinal glia, with a pattern similar to that of TNF-α. TrkC.T1(-/-) mice had normal retinas. However, during experimental glaucoma, TrkC.T1(-/-) mice had lower rates of RGC death and produced less TNF-α than wild-type littermates. In rats with glaucoma, the pharmacologic use of TrkC antagonists delayed RGC death and reduced the production of retinal TNF-α. CONCLUSIONS:TrkC.T1 is implicated in glaucomatous RGC death through the control of glial TNF-α production. Overall, the data point to a paracrine mechanism whereby elevated intraocular pressure upregulated glial TrkC.T1 expression in glia; TrkC.T1 controlled glial TNF-α production, and TNF-α caused RGC death.
journal_name
Invest Ophthalmol Vis Scijournal_title
Investigative ophthalmology & visual scienceauthors
Bai Y,Shi Z,Zhuo Y,Liu J,Malakhov A,Ko E,Burgess K,Schaefer H,Esteban PF,Tessarollo L,Saragovi HUdoi
10.1167/iovs.10-5431subject
Has Abstractpub_date
2010-12-01 00:00:00pages
6639-51issue
12eissn
0146-0404issn
1552-5783pii
iovs.10-5431journal_volume
51pub_type
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