Increased <scp>D</scp>‐serine in the aqueous and vitreous humour in patients with proliferative diabetic retinopathy

Jiang, Haiyan; Du, Jinlin; He, Tao; Qu, Jia; Song, Zongming; Wu, Shengzhou

doi:10.1111/ceo.12329

Cited by 15 publications

(9 citation statements)

References 19 publications

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“…d ‐serine from retina and RPE tissue of mice was detected with reverse‐phase HPLC by a method similar to that reported (Jiang et al . ). Trichloroacetic acid (10%) was used to precipitate the tissue homogenates, which were cleared by centrifugation.…”

Section: Methodsmentioning

confidence: 97%

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Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Jiang

Liu

et al. 2017

Journal of Neurochemistry

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Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide ( NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR-coding gene (Srr ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srr mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more inducible NOS, produced more NO and VEGF than did inflammation-primed Srr RPEs. When co-cultured with inflammation-primed Srr RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser-induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis.

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Section: Methodsmentioning

confidence: 97%

“…In contrast, the physiological and pathological roles of SR/ d ‐serine in the retina are relatively scant, but SR/ d ‐serine has been implicated in diabetic retinopathy (Jiang et al . , , ). SR expression has been reported in retinal ganglion cells and glial cells (Stevens et al .…”

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confidence: 99%

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Jiang

Liu

et al. 2017

Journal of Neurochemistry

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“…In addition, recently Jiang et al [ 16 ] found an increased level of D-serine in the aqueous and vitreous humour of PDR patients. Earlier, the same group reported high level of serine racemase, D-serine and glutamate in the diabetic eye [ 17 ].…”

Section: Glutamatementioning

confidence: 99%

Neurodegeneration in Diabetic Retina and Its Potential Drug Targets

Ola¹,

Alhomida

2014

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Diabetic retinopathy (DR) is one of the major complications of diabetes causing vision loss and blindness worldwide. DR is widely recognized as a neurodegenerative disease as evidenced from early changes at cellular and molecular levels in the neuronal component of the diabetic retina, which is further supported by various retinal functional tests indicating functional deficits in the retina soon after diabetes progression. Diabetes alters the level of a number of neurodegenerative metabolites, which increases influx through several metabolic pathways which in turn induce an increase in oxidative stress and a decrease in neurotrophic factors, thereby damage retinal neurons. Loss of neurons may implicate in vascular pathology, a clinical signs of DR observed at later stages of the disease. Here, we discuss diabetes-induced potential metabolites known to be detrimental to neuronal damage and their mechanism of action. In addition, we highlight important neurotrophic factors, whose level have been found to be dysregulated in diabetic retina and may damage neurons. Furthermore, we discuss potential drugs and strategies based on targeting diabetes-induced metabolites, metabolic pathways, oxidative stress, and neurotrophins to protect retinal neurons, which may ameliorate vision loss and vascular damage in DR.

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“…Our prior results indicate that increased SR expression in retina and the elevated levels of retinal/aqueous D‐serine are correlated with DR (Jiang et al . , ). In this study, we provide direct evidence that loss‐of‐function of mutation of SR protects against excitotoxicity in retina, suggesting novel therapeutic approaches to ameliorate neurodegeneration in DR.…”

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confidence: 99%

Loss‐of‐function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N‐methyl‐D‐aspartate

Jiang

Wang

Zhang

et al. 2015

Journal of Neurochemistry

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Convincing data demonstrate that D-serine, a racemized product of serine racemase (SR), contributes to neurotoxicity. Furthermore, a line of evidence suggests that SR/D-serine contributes to retinal neurodegeneration in a diabetic retinopathy rat model and diabetic retinopathy patients. However, the connection between SR/D-serine and retinal neurodegeneration remains unclear. Herein, we report that intravitreal injection of N-methyl-D-aspartate (NMDA) induces excitotoxicity in rodent retina; this retinal neurodegeneration was attenuated in retina carrying a loss-of-function of mutation in Srr, the gene for SR, termed Srr ochre269 . Under the condition of NMDA injection, either posterior pole or middle -but not peripheral -retina from Srr ochre269 mice was found to retain more retinal ganglion cells (RGC) than the counterpart from w/t (RGCs were identified with retrograde labeling). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining further demonstrated reduced RGC apoptosis from Srr ochre269 compared to w/t mice under the condition of NMDA injection. Collectively, our studies demonstrate a pivotal role of SR/D-serine in retinal neurotoxicity.

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Increased D‐serine in the aqueous and vitreous humour in patients with proliferative diabetic retinopathy

Abstract: Increased D-serine in the aqueous and vitreous humour was found in patients with PDR compared with control subjects.

Cited by 15 publications

References 19 publications

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells

Neurodegeneration in Diabetic Retina and Its Potential Drug Targets

Loss‐of‐function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N‐methyl‐D‐aspartate

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