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Yonju Ha, Alan Saul, Cory Williams, Eric Zorrilla, Vadivel Ganapathy, Sylvia B. Smith; Increased Susceptibility to Retinal Stress in Mice Lacking Sigma Receptor 1 (R1). Invest. Ophthalmol. Vis. Sci. 2012;53(14):6417.
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σR1 is a non-opioid transmembrane protein that may act as a molecular chaperone at the ER-mitochondrial membrane. Ligands for σR1 confer marked retinal neuroprotection in vivo and in vitro. Recently, we analyzed the retinal phenotype of mice lacking σR1 (σR1-KO) and observed normal retinas (morphologically and functionally) in young mice (5-30) weeks, but diminished negative scotopic threshold responses (nSTR), ganglion cell (GC) loss and disruption of optic nerve axons consistent with inner retinal dysfunction in mice by 1 year (Ha et al, 2011). These data led us to test the hypothesis that σR1 may be critical in forestalling long-term retinal stress.
In vitro: 1°GCs were isolated from WT and σR1 KO mice per our method (Ha et al, 2011) and were exposed to 10 nM TNF-α, an inflammatory cytokine, for 3, 6, 18, 24, 48 h. Cell death was evaluated by TUNEL analysis. In vivo: Stress in the form of diabetes (DB) was induced in 3 wk C57Bl/6 (WT) and σR1-KO mice using streptozotocin (75 mg/kg, 3 days) to yield 4 groups: WT-DB, WT-nonDB, σR1-KO-DB, σR1-KO-nonDB. After 10-12 wks diabetes duration, intraocular pressure (IOP) was recorded mid-day & midnight; electrophysiological testing was performed including detection of nSTRs, which are generated largely by GCs.
In vitro: Exposure of σR1-KO 1°GCs to TNF-α for 48 resulted in 37% more cell death than in TNF-α treated WT 1°GCs (25.9 ± 1.2 % versus 16.3 ± 1.2%). In vivo: The average IOP measured in σR1-KO-DB mice was significantly higher than in other groups (σR1 KO-non-DB, WT-non-DB, WT-DB): 16 mm Hg versus ~12 mm Hg. nSTRs were significantly decreased in σR1-KO-DB mice (5 ± 1µV) compared to the other groups, notably σR1-KO-nonDB (12 ± 2 µV).
Absence of σR1 appears to increase susceptibility to stress. In vitro, retinal neurons isolated from mice lacking σR1 do not withstand cytokine insult as well as those isolated from WT mice. Moreover, in vivo stress accelerates the functional deficits in σR1 KO mice such that ganglion cell dysfunction is observed at a much earlier age in diabetic σR1 KO mice compared to non-diabetic σR1 KO mice. The data support the hypothesis that σR1 plays a key role in stress tolerance in retina.
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