| First Author | Ha Y | Year | 2012 |
| Journal | Mol Vis | Volume | 18 |
| Pages | 2860-70 | PubMed ID | 23233788 |
| Mgi Jnum | J:192545 | Mgi Id | MGI:5465361 |
| Citation | Ha Y, et al. (2012) Diabetes accelerates retinal ganglion cell dysfunction in mice lacking sigma receptor 1. Mol Vis 18:2860-70 |
| abstractText | PURPOSE: Sigma receptor 1 (sigmaR1) is a non-opioid transmembrane protein that may act as a molecular chaperone at the endoplasmic reticulum-mitochondrial membrane. Ligands for sigmaR1, such as (+)-pentazocine [(+)-PTZ], confer marked retinal neuroprotection in vivo and in vitro. Recently we analyzed the retinal phenotype of mice lacking sigmaR1 (sigmaR1 KO) and observed normal retinal morphology and function in young mice (5-30 weeks) but diminished negative scotopic threshold responses (nSTRs), retinal ganglion cell (RGC) loss, and disruption of optic nerve axons consistent with inner retinal dysfunction by 1 year. These data led us to test the hypothesis that sigmaR1 may be critical in forestalling chronic retinal stress; diabetes was used as the model of chronic stress. METHODS: To determine whether sigmaR1 is required for (+)-PTZ neuroprotective effects, primary RGCs isolated from wild-type (WT) and sigmaR1 KO mice were exposed to xanthine-xanthine oxidase (10 microM:2 mU/ml) to induce oxidative stress in the presence or absence of (+)-PTZ. Cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. To assess effects of chronic stress on RGC function, diabetes was induced in 3-week C57BL/6 (WT) and sigmaR1 KO mice, using streptozotocin to yield four groups: WT nondiabetic (WT non-DB), WT diabetic (WT-DB), sigmaR1 KO non-DB, and sigmaR1 KO-DB. After 12 weeks of diabetes, when mice were 15-weeks old, intraocular pressure (IOP) was recorded, electrophysiologic testing was performed (including detection of nSTRs), and the number of RGCs was counted in retinal histological sections. RESULTS: In vitro studies showed that (+)-PTZ could not prevent oxidative stress-induced death of RGCs harvested from sigmaR1 KO mice but afforded robust protection against death of RGCs harvested from WT mice. In the studies of chronic stress induced by diabetes, the IOP measured in the four mouse groups was within the normal range; however, there was a significant increase in the IOP of sigmaR1 KO-DB mice (16 +/- 0.5 mmHg) compared to the other groups tested (sigmaR1 KO non-DB, WT non-DB, WT-DB: ~12 +/- 0.6 mmHg). Regarding electrophysiologic testing, the nSTRs of sigmaR1 KO non-DB mice were similar to WT non-DB mice at 15 weeks; however, they were significantly lower in sigmaR1 KO-DB mice (5 +/- 1 microV) compared to the other groups, including, notably, sigmaR1 KO-nonDB (12+/-2 microV). As expected, the number of RGCs in sigmaR1 KO non-DB mice was similar to WT non-DB mice at 15 weeks, but under chronic stress of diabetes there were fewer RGCs in retinas of sigmaR1 KO-DB mice. CONCLUSIONS: This is the first report showing unequivocally that the neuroprotective effects of (+)-PTZ require sigmaR1. sigmaR1 KO mice show normal retinal structure and function at young ages; however, when subjected to the chronic stress of diabetes, there is an acceleration of retinal functional deficits in sigmaR1 KO mice such that ganglion cell dysfunction is observed at a much earlier age than nondiabetic sigmaR1 KO mice. The data support the hypothesis that sigmaR1 plays a key role in modulating retinal stress and may be an important target for retinal disease. |
