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Role of Sigma 1 Receptor in Retinal Degeneration of the Ins2 Akita/Þ

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Role of Sigma 1 Receptor in Retinal Degeneration of the Ins2 Akita/Þ Retinal Cell Biology Role of Sigma 1 Receptor in Retinal Degeneration of the Ins2Akita/þ Murine Model of Diabetic Retinopathy Jing Wang,1,2 Xuezhi Cui,1,2 Penny Roon,1 and Sylvia B. Smith1–3 1Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, United States 2The James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States 3Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States Correspondence: Sylvia B. Smith, PURPOSE. Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has Department of Cellular Biology and neuroprotective properties in retina. This study sought to determine whether delaying Anatomy, Medical College of Geor- administration of (þ)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in gia, Augusta University, 1120 15th Ins2Akita/þ diabetic mice would afford retinal neuroprotection and to determine conse- Street, CB 1114, Augusta, GA 30912- quences on retinal phenotype in Akita/þ diabetic mice in the absence of Sigma1R. 2000, USA; Ins2 [email protected]. METHODS. Ins2Akita/þ diabetic and WT mice received intraperitoneal injections of (þ)- JW and XC contributed equally to the pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. work presented here and should Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of therefore be regarded as equivalent ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). authors. Ins2Akita/þ/Sig1RÀ/Àmice were generated and subjected to in vivo assessment of retinal JW and XC are joint first authors. architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2Akita/þ mice. Eyes were Submitted: December 21, 2015 then harvested for retinal morphometric assessment and gliosis assessment. Accepted: April 17, 2016 Akita/þ Citation: Wang J, Cui X, Roon P, Smith RESULTS. Wild-type mice had 13 6 0.06 cells/100 lm retinal length; cell bodies in Ins2 SB. Role of Sigma 1 Receptor in retinal mice injected 4 and 8 weeks after onset of diabetes with (þ)-pentazocine retained degeneration of the Ins2Akita/þ mu- significantly more ganglion cells compared with Ins2Akita/þ mice (9 6 0.04) and rine model of diabetic retinopathy. demonstrated significant attenuation of gliosis. Ins2Akita/þ/Sig1RÀ/Àmouse retinas, analyzed Invest Ophthalmol Vis Sci. to determine whether the Ins2Akita/þ phenotype was accelerated when lacking Sigma1R, 2016;57:2770–2781. DOI:10.1167/ revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel iovs.15-18995 beading (FA) compared with Ins2Akita/þ mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2Akita/þ/Sig1RÀ/Àmice compared with Ins2Akita/þ mice. CONCLUSIONS. Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection. Keywords: retina, sigma 1 receptor (r1R), ganglion cells, GFAP, (þ)-pentazocine, OCT, fluorescein angiography, FA, mouse iabetic retinopathy is a leading cause of sight-threatening there is at least 20% reduction in the number of cell bodies in D disabilities worldwide.1 Evidence compiled from clinical the retinal GCL of these diabetic mice as they age.5 Although and basic research investigations supports the view that this model has increased retinal vascular permeability and a diabetic retinopathy constitutes a change in the retinal modest increase in acellular capillaries after approximately 8 neurovascular unit, which specifically refers to neurons, glia, months, the classical vascular pathology as assessed by and vasculature.2 The vascular pathology in diabetic retinopa- scanning laser ophthalmoscopy (SLO), fluorescein angiography thy involves occlusion of retinal vessels and leakiness that can (FA), and optical coherence tomography (OCT) is not result in macular edema, frequently associated with severe prominent in this mouse model.7 vision loss.3 Retinal neurons and glial cells are also altered in Several years ago, our laboratory used the Ins2Akita/þ mouse diabetic retinopathy as microvascular lesions develop, espe- to investigate whether targeting a unique protein, sigma 1 cially loss of neurons in the ganglion cell layer (GCL) and the receptor (Sigma1R), would attenuate ganglion cell loss.8 We inner nuclear layer (INL).4 A mouse model that has proven found that sustained administration of a high-affinity Sigma1R useful for studies of the retinal neuronal phenotype associated ligand, (þ)-pentazocine [(þ)-PTZ] conferred significant retinal with diabetes is the Ins2Akita/þ mouse.5 This mouse has a point neuroprotection, reduced evidence of oxidative stress, and mutation in the Ins2 gene causing a conformational change in preserved retinal architecture. In particular, ganglion cell death the protein, which accumulates in the b cells of the pancreas, was markedly reduced in (þ)-PTZ–treated Ins2Akita/þmice, inducing cell death.6 The homozygous mice are rarely viable, suggesting that SigmaR1 ligands are promising therapeutic but the heterozygous mice develop hyperglycemia, hypoinsu- agents for intervention in neurodegenerative diseases of the linemia, polydipsia, and polyuria at approximately 4 weeks. retina, including diabetic retinopathy. Subclinical changes occur in the retina of Ins2Akita/þ, consistent Sigma1R is 223-amino-acid nonopioid protein that shares no with the prodromal phase of diabetic retinopathy. Most notably, homology with any other mammalian protein. It is a unique iovs.arvojournals.org j ISSN: 1552-5783 2770 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 10/02/2021 Sigma1R and Ins2Akita/þ Mouse IOVS j May 2016 j Vol. 57 j No. 6 j 2771 TABLE 1. Average Weights and Blood Glucose Levels of Mice Used in the Delayed (þ)-PTZ Administration Study Mouse Strain and Blood Glucose 6 SEM Age When (þ)-PTZ Treatment Group n Mean Weight 6 SEM (g) (mg/dL) Injection Began (wk) WT (Ins2þ/þ) [no (þ)-PTZ] 6 25.96 6 2.65 197.0 6 46.5 * WT (Ins2þ/þ) [0.5 mg kgÀ1 (þ)-PTZ] 8 25.60 6 3.10 116.6 6 55.9 8 Ins2Akita/þ [no (þ)-PTZ] 5 22.91 6 0.66 487.0 6 26.0 * Ins2Akita/þ [0.5 mg kgÀ1 (þ)-PTZ] 5 20.82 6 5.08 474.5 6 51.0 8 Ins2Akita/þ [0.5 mg kgÀ1 (þ)-PTZ] 4 18.02 6 1.66 376.7 6 99.3 12 * These mice received no (þ)-PTZ injection. integral membrane protein.9 Aside from N,N-dimethyltrypta- verified by measuring urine glucose using the Diastic Reagent mine,10 no natural ligands for Sigma1R have been identified. Strips for urinalysis (Bayer, Mishawaka, IN, USA) and blood Sigma1R is a putative molecular chaperone11 that regulates glucose using a Blood Glucose Monitoring System (Abbott Ca2þ mobilization from endoplasmic reticulum (ER) stores12 Laboratories, Alameda, CA, USA). Fasting blood glucose levels and contributes to the stability of inositol 1,4,5-triphosphate >240 mg/dL were considered diabetic. Diabetic animals were type 3 receptor channels to ensure proper Ca2þ transport not maintained on insulin. Age-matched, nondiabetic WT mice between the ER and the mitochondrial-associated membrane.13 were used as controls. All mice received food and water ad These cellular survival properties have prompted speculation libitum and were maintained on a 12-hour light-dark cycle. Body that ligands for Sigma1R could be promising for treatment of weight and blood glucose were measured at time of death, and neurodegenerative diseases,14 including retinal diseases. Sig- data are provided in Tables 1 and 2. ma1R is present in several ocular tissues including retina,15–20 Two studies were conducted. In the first study, we examined cornea, ciliary body, and lens.15,20 A number of in vitro and in the effects of delaying (þ)-PTZ injection (after onset of diabetes) vivo studies demonstrate the powerful neuroprotective effects on retinal neuronal death in diabetic retinopathy. Details of (þ)- of Sigma1R ligands, most notably in protection against retinal PTZ injections are provided below. In the second study, we ganglion cell death.8,21–24 Ligands for Sigma1R modulate ER determined whether the retinal neurodegeneration of Ins2Akita/þ stress in retinal ganglion cells25 and ER stress and osmolar mice would be accelerated if the mice lacked Sigma1R, and we stress in retinal Muller¨ glia cells26,27; they also regulate asked whether the retinal phenotype would involve vasculop- intracellular Ca2þ calcium levels in retinal ganglion cells.28 athy when Sigma1R was absent. C57BL/6-Ins2Akita/J mice were 29 Studies from Tchedre et al. provide evidence that Sigma1R bred with Sig1RÀ/À mice (the generation of which has been 2 interacts directly with voltage-gated Ca þcalcium channels in previously described30,32)toproduceIns2Akita/þ/Sig1R6 mice, primary cultures of ganglion cells. Mice lacking Sigma1R which were crossed with Sig1RÀ/À mice to generate Ins2Akita/þ/ À/À (Sig1R mice) have a late-onset retinal degeneration charac- Sig1RÀ/Àmice. Genotyping was performed to confirm gene 30 terized by loss of ganglion cells. Under stress, such as optic expression in all mice. In addition, we confirmed that the mice 18 31 À/À nerve crush or streptozotocin-induced diabetes in Sig1R did not carry the rd8 (Crb1) mutation, which manifests as mice, there is acceleration of the ganglion cell loss. disrupted morphology including retinal rosettes.33 Mice were The finding that ligands for Sigma1R were neuroprotective in maintained for either 12 or 16 weeks, after which they were Akita/þ 8 Ins2 mice combined with the observation that strepto- subjected to functional and morphologic analysis. Maintenance À/À zotocin-induced diabetes accelerated the phenotype in Sig1R of animals adhered to the institutional guidelines for the humane mice prompted the present investigation.
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