recent progress in molecular biology has revealed the molecular basis in the pathogenesis of various diseases . one such therapy is antivascular endothelial growth factor ( anti - vegf ) therapy , which is now widely used to treat age - related macular degeneration ( amd ) and cancer . its role in treating amd is to regulate ocular vascular lesions and prevent secondary damage to the neural retinal cells , which are critical for visual function . the first research into vegf was reported in the 1970s , and in 2004 the fda approved the first anti - vegf drug for clinical use in human eyes     . basic research on neurotrophic regulation also began in the 1970s , but clinical trials started only recently     . molecular - targeting therapies for retinal neuroprotection are on the horizon , and further studies are needed to understand the molecular mechanisms in retinal diseases and to explore new treatment approaches . in the treatment of retinal diseases , developing neuroprotective therapies for neural retinal cells deserves special emphasis ; these cells have a very limited regenerative capacity and are critical to vision . the neural retinal cells derive from the monolayer of the neural tube during embryogenesis and are part of the central nervous system . damage to these cells occurs in common diseases such as chorioretinal inflammation and diabetic retinopathy , as well as in less - common conditions , like retinitis pigmentosa , a hereditary retinal degeneration with mutated genes in the retinal cells . diabetes chronically affects it , even in the absence of obvious microangiopathy     [ 68 ] : patients experience a gradual loss of visual function even when diabetic neovascularization is well regulated by vitreous surgery and/or anti - vegf therapy . in amd , local retinal inflammation is involved in the process of vision loss ; association of inflammatory molecules is reported in both early and late stage amd . however , the investigation of the molecular mechanisms of retinal neuropathogenesis is in its early stages . here , we describe the molecular mechanism of neurodegeneration that we recently reported in animal models of innate chorioretinal inflammation ( endotoxin - induced uveitis ) and diabetic retinopathy , and compare our findings with studies from other fields to obtain additional clues to the pathogenesis of retinal diseases . clinical reports show that il-6 in the vitreous fluid increases not only in uveitis   but also in diabetic retinopathy    [ 11 , 12 ] , retinal vein occlusion    , and retinal detachment . research with experimental animals has shown that diffusible factors , il-6 and other proteins in the il-6 family , such as leukemia inhibitory factor ( lif ) and ciliary neurotrophic factor ( cntf ) , are expressed in the retina . both il-6      and lif      are found in mller glial cells , and cntf is found in the retinal ganglion cells and astrocytes around the vessels     . these endogenous il-6 family proteins are upregulated during inflammation and function to promote pathogenesis of the vascular system     . il-6 family proteins use cytokine - specific receptors to activate a transmembrane receptor , gp130 , which then recruits janus kinase ( jak ) to activate transcription factor signal transducer and activator of transcription 3 ( stat3 ) . stat3 then regulates various molecules at the transcriptional level , including suppressor of cytokine signaling 3 ( socs3 ) . socs3 acts as a negative feedback modulator of stat3 by inhibiting jak and subsequent stat3 activation   ( figure 1 ) . in the retina , socs3 is expressed in the photoreceptor cells , mller glial cells , and retinal ganglion cells , and it inhibits stat3 activation in these cells     [ 21 , 22 ] . since stat3 activation induces further stat3-activating factors , such as the il-6 family ligands     , the balance between stat3 activation and socs3 level is one of the key determinants of an inflammatory reaction     [ 23 , 24 ] . this balance between stat3 and socs3 also plays an important role during the development of the retina ; activated stat3 inhibits the photoreceptor - specific transcription factor crx at the transcriptional level , which in turn inhibits downstream photoreceptor - specific markers such as rhodopsin     . retina - specific conditional knockout mice of socs3 , -cre socs3 flox / flox mice ( socs3cko ) , induce increase in the endogenous stat3 activation , and show delay in the initiation of rhodopsin expression at the transcriptional level     . stat3 is activated in the embryonic retina but is shut down by socs3 which appears in the neonatal retina , thereby allowing rod photoreceptor cell differentiation . therefore , the timing of rod photoreceptor cell differentiation is fine - tuned by the initiation of socs3 expression and downregulation of stat3 activation . although stat3 activation in the socs3cko retina is still upregulated in the adulthood , the rhodopsin level in the socs3cko mice is compensated for by as - yet - unknown mechanisms and matches that of wild - type mice . a murine model of accelerated innate immunity , the endotoxin - induced uveitis model ( eiu model ) , was used to further analyze the role of the gp130-stat3-socs3 loop in adult retinal inflammation . in this model , inflammatory cytokine , il-6 is upregulated     , leading to stat3 activation     [ 21 , 26 , 27 ] in the retina . this induction does not cause retinal cellular apoptosis , but it does reduce visual function     [ 21 , 26 , 27 ] : rhodopsin protein levels decrease , and the rod photoreceptor outer segments ( oss ) , where rhodopsin is concentrated , are shortened . the scotopic electroretinogram ( erg ) a - wave amplitude , which represents rod photoreceptor cell function , also decreases . stat3 activation correlates with the rhodopsin reduction in the adult retina , as in the developing retina . surprisingly , though , neither rhodopsin mrna nor its upstream regulator , crx , decreases in the adult retina during inflammation . this suggests that a different mechanism is involved in rhodopsin and crx regulation in the adult retina than in the developing retina     [ 22 , 25 ] . the role of activated stat3 in retinal dysfunction during inflammation has been analyzed using socs3cko mice     . in these socs3-deficient mice , stat3 activation can increase greatly in the retina ( figures 2(a ) and 2(c ) ) . thus , we have hypothesized that the mechanism of rhodopsin reduction during inflammation might be enhanced in these cells . as expected , the eiu models generated in the adult socs3cko mice showed a relative depletion of rhodopsin protein ( figures 2(b ) and 2(d ) ) , followed by os shortening . the subsequent rod photoreceptor cell dysfunction , as measured by scotopic erg , was prolonged . this model also revealed that during inflammation , rhodopsin reduction is not regulated at the transcriptional level , but by a post - transcriptional inhibitory mechanism . the reduction in rhodopsin protein levels is rapid and global , starting only several hours from the onset of inflammation . under stress conditions , massive protein degradation through the ubiquitin - proteasome system ( ups ) is known to increase     . a genetically abnormal rhodopsin protein that causes autosomal dominant retinitis pigmentosa , p23h , interacts with the ups and forms aggresomes aggresomes are inclusion bodies of accumulated waste proteins , formed when cellular degradation machinery is impaired or overwhelmed , and they are a pathologic finding in neurodegenerative diseases . in the case of p23h , the rhodopsin protein folds abnormally and accumulates rather than following the normal process of elimination from the cell . this finding hinted that genetically normal rhodopsin protein might also be degraded extensively following the excessive induction of the ups by inflammation . moreover , ubiquitin is present in the rod os under control conditions     , thus it can rapidly degrade rhodopsin as needed . elevated levels of ubiquitin - conjugated rhodopsin are followed by rhodopsin depletion in the socs3cko eiu mouse model . the same process occurs in wild - type mice , but it is more rapid and more severe in the socs3cko mice , in which stat3 activation is increased . therefore , the activated stat3 level correlates with the ubiquitination and degradation of rhodopsin . this has been confirmed in vitro by using jak inhibitor to inhibit il-6-induced stat3 activation . it is illustrated by the preservation of rhodopsin levels under il-6-induced stat3 activation , when a stat3-dependent ubiquitin e3 ligase , ubiquitin - protein ligase e3 component n - recognin 1 ( ubr1 ) , is inhibited through the small inhibitory rna ( sirna ) system . we propose that it contributes to rhodopsin protein degradation during inflammation , especially given that inflammatory cytokines , including il-6 , lif , and cntf , induce the ubiquitin - conjugation of rhodopsin protein and ubr1 expression in the rod photoreceptor cells , resulting in excessive rhodopsin degradation and disturbed visual functioning ( figure 3 ) . stat3 can be activated not only through the gp130 receptor , but also through an inflammatory diffusible factor , angiotensin ii . an angiotensin ii type 1 receptor blocker ( arb ) suppresses stat3 activation      during inflammation directly , or indirectly , inhibiting il-6 production , thereby preserving rhodopsin levels and visual function . angiotensin ii also induces oxidative stress , which can induce the ubiquitination of specific proteins . the antioxidant lutein , which suppresses oxidative stress and the induction of reactive oxygen species ( ros ) during inflammation , also reduces stat3 activation , thus preserving the rhodopsin level and visual function during inflammation     . therefore , the mechanism of visual dysfunction is , at least in part , explained by the excessive degradation of the essential protein during inflammation . in diabetic retinopathy , the main findings include microangiopathy     [ 33 , 34 ] and neurodegeneration     [ 35 , 36 ] . visual dysfunction begins before vascular abnormalities become obvious     [ 68 ] , and inner retinal dysfunction is reflected in changes in erg oscillatory potentials ( ops ) ( figure 4 ) . however , little is known about the molecular mechanism of diabetes - related neuronal degeneration . our recent analyses using a streptozotocin- ( stz- ) induced type 1 diabetes model shed light on this critical issue     [ 35 , 36 ] . both diabetes and hypertension are involved in metabolic syndrome , in which angiotensin ii signaling plays an important role . arbs have been approved for treatment of not only high blood pressure , but also diabetes - related renal failure     . angiotensin ii is converted from angiotensinogen in a stepwise fashion by enzymes , including renin , angiotensin converting enzyme , and others . angiotensin ii can bind to either the angiotensin ii type 1 receptor ( at1r ) or type 2 receptor ( at2r ) on the cell surface , which in turn activates several contextually - dependent intracellular signals . these components of the rennin angiotensin system ( ras ) are all present physiologically in the retina , and are upregulated in pathological conditions , as we have shown in the murine model retina of stz - induced diabetes     . at1r is coexpressed with the major synaptic vesicle protein synaptophysin in the inner layers of the retina     . this is consistent with several previous reports showing the synaptic expression of at1r in the brain     [ 38 , 39 ] . synaptophysin , a synapse marker , is reduced in the postmortem brains of patients who had had neurodegenerative diseases such as parkinson 's disease and alzheimer 's disease . given that the ops in erg originate from inner retinal neurons bearing at1r , these erg changes may represent angiotensin ii - induced synaptophysin dysregulation and the resulting damage to visual function . we have verified this hypothesis by administering arb ( either telmisartan or valsartan ) to stz - induced diabetic mice     . arbs protect the expression of synaptophysin protein and ops in the diabetic retina ( figure 4 ) . interestingly , synaptophysin mrna is not reduced in the diabetic retina , indicating that the protein 's reduction is regulated post - transcriptionally . post - transcriptional synaptophysin reduction caused by angiotensin ii exposure was reproduced in a rat neuronal cell line , pc12     . in this system , synaptophysin protein degradation is inhibited by the proteasome inhibitor mg132 , but not the lysosome inhibitor e64 . at1r and its downstream extracellular signal - related protein kinase ( erk ) activation induce synaptophysin degradation , and at1r increases the ubiquitin - conjugated synaptophysin protein levels . angiotensin ii signaling activates erk in the diabetic retina in vivo , suggesting that the at1r - erk pathway is responsible for diabetes - induced pathogenic protein degradation through the ups . synaptophysin protein may be degraded by the mammalian homolog of drosophila seven in absentia ( sina ) , an e3-ligase selective for synaptophysin named seven in absentia homologue ( siah ) . since drosophila sina is regulated by erk signaling     , the siah may also be regulated by erk activation , which is increased in the diabetic retina . erk activation and the resulting reduction of synaptophysin in the diabetic retina is also inhibited by an antioxidant , lutein , which indicates that angiotensin ii signaling and oxidative stress may share a role in the pathogenesis of diabetic retinopathy . not only that the reduction of synaptophysin , a synaptic protein , impairs the transmission of neuronal and visual signals , but impairment of synaptic activity itself inhibits neuronal cell survival [ 34 , 35 ] . synaptic activity , that is , the neuronal electric stimuli , directly increases the levels of intracellular calcium ion in neurons , which promotes cell survival . moreover , brain - derived neurotrophic factor , bdnf , a neuronal survival factor , is regulated by neuronal synaptic activity [ 37 , 38 ] . taken together , these findings suggest that the synaptophysin levels and the related neuronal synaptic activity function together to influence neuronal survival and neuronal network activity . the reduction of synaptophysin levels and neuronal activity , observed 1 month after the onset of diabetic retinopathy , is later followed by the apoptosis of retinal ganglion cells and inner retinal cells . therefore , one part of the neurodegenerative mechanism in the diabetic retina is explained by the excessive degradation of a protein that is essential for visual function ( figure 5 ) . the ups is a rapid and effective method of degrading specific proteins , and in many cases a protein is degraded only in response to a particular cellular signal or event . this process involves the coordinated actions of three enzymes  a generally distributed e1 ubiquitin - activating enzyme , several more specific e2 ubiquitin - conjugating enzymes , and highly specific e3 ubiquitin ligases for the targeted protein . the ups involvement in pathogenesis has led to interest in targeting proteasomes as a therapeutic approach in several fields . ups is involved in cardiomyocyte cell pathogenesis : oxidized and ubiquitinated proteins are observed in rat hearts after cardiac ischemia / reperfusion injury     [ 43 , 44 ] . muscle wasting due to ups activation is also reported in cases of chronic kidney disease , diabetes , high angiotensin ii levels , and sepsis , all of which cause inflammation , inhibit insulin signaling , and promote glucocorticoid expression to induce protein degradation     [ 4547 ] . this pathway can be blocked by overexpressing igf-1 , which inhibits atrogin-1 , an e3-ligase acting for muscle atrophy , through pi3k / akt     [ 46 , 48 ] .   in the retina , innate inflammation activates the il-6-stat3 pathway , and diabetes activates the angiotensin ii - erk pathway . both pathways induce the ups , most likely through inducing a specific e3-ligase . moreover , both pathogenic conditions induce oxidative stress     [ 27 , 36 ] , which oxidizes and unfolds proteins , after which they are easily ubiquitinated and pushed into the ups pathway . in contrast , modification of the 20s proteasome subunits by the lipid peroxidation product 4-hydroxy-2-nonenal ( hne ) , which occurs in cardiac ischemia / reperfusion , results in the selective inactivation of 20s activity . thus , modified and ubiquitinated proteins may accumulate to induce cell death in some pathological conditions . the ups degrades numerous proteins , including apoptotic proteins , and regulates multiple signaling pathways . in human - dilated cardiomyopathy , the increased expression of the proapoptosis regulator p53 has recently been associated with ups dysregulation and accumulation of polyubiquitinated proteins     . therefore , the above findings show that the ups , a selective and bulk protein degradation system , may be modified through multiple pathways . this system excessively degrades proteins necessary for tissue - specific function and/or cell survival , causing tissue pathogenesis . however , if this system is overwhelmed and/or dysregulated , modified proteins can accumulate and damage the cells . in inflammation , protein degradation damages tissue function , while it may also protect tissue from pathogenic protein accumulations . since the ups acts on specific proteins , regulating it may improve the prognosis . bortezomib , a dipeptide boronic acid , is the first fda - approved proteasome inhibitor for the treatment of multiple myeloma     . bortezomib directly induces cell - cycle arrest and apoptosis , and it targets the tumor microenvironment . combination chemotherapy regimens using bortezomib have been developed that provide high rates of long - lasting remissions . interestingly , in patients treated with bortezomib , proteasome inhibition improves myocardial ischemia / reperfusion injuries , prevents postischemic ventricular tachyarrhythmias , promotes cardiac hypertrophy regression , and reverses diabetes - induced vascular endothelial dysfunction     [ 52 , 53 ] . proteasome inhibition can be also applied locally . in a balloon injury model of the rat carotid artery , a locally administered proteasome inhibitor , in addition to bortezomib , another proteasome inhibitor , sorafenib has been also approved by fda for advanced cancer therapy , and another candidate reagent is now under trial . in view of the potential therapeutic benefit of ups regulation inflammatory retinal diseases , including diabetic retinopathy , induce inflammatory cytokines that influence protein metabolism . excessive degradation of tissue function essential proteins is an important factor in retinal neuronal dysfunction . further analyses of the mechanisms that impair visual function may lead us to new therapeutic approaches for retinal neuroprotection .