Update on genetics and diabetic retinopathy

Hampton, Blake M; Schwartz, Stephen G.; Brantley, Milam A.; Flynn, Harry W.

doi:10.2147/opth.s94508

Cited by 35 publications

(29 citation statements)

References 134 publications

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“…VEGF has been considered to be an important factor in the pathogenesis of DR in response to high glucose or other stimulus, and it can activate VEGFR-1 and -2, which triggers a signaling cascade promoting endothelial cells migration and sprouting (1,7). PGF that upregulates the expression of VEGFA and other angiogenic factors has been shown to be associated with ischemia or wound stimulated angiogenesis and tumor angiogenesis (23).…”

Section: Discussionmentioning

confidence: 99%

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Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment

Zhao

Peng

et al. 2017

Braz J Med Biol Res

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Diabetic retinopathy (DR) is one of the common and specific microvascular complications of diabetes. This study aimed to investigate the anti-angiogenic effect of kaempferol and explore its underlying molecular mechanisms. The mRNA expression level of vascular endothelial growth factor (VEGF) and placenta growth factor (PGF) and the concentrations of secreted VEGF and PGF were measured by qTR-PCR and ELISA assay, respectively. Human retinal endothelial cells (HRECs) proliferation, migration, and sprouting were measured by CCK-8 and transwell, scratching wound, and tube formation assays, respectively. Protein levels were determined by western blot. High glucose (25 mM) increased the mRNA expression levels of VEGF and PGF as well as the concentrations of secreted VEGF and PGF in HRECs, which can be antagonized by kaempferol (25 µM). Kaempferol (5-25 µM) significantly suppressed cell proliferation, migration, migration distance and sprouting of HRECs under high glucose condition. The anti-angiogenic effect of kaempferol was mediated via downregulating the expression of PI3K and inhibiting the activation of Erk1/2, Src, and Akt1. This study indicates that kaempferol suppressed angiogenesis of HRECs via targeting VEGF and PGF to inhibit the activation of Src-Akt1-Erk1/2 signaling pathway. The results suggest that kaempferol may be a potential drug for better management of DR.

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Section: Discussionmentioning

confidence: 99%

“…Diabetic retinopathy (DR) is one of the common and specific microvascular complications of diabetes and is also the leading cause of new-onset blindness in the developed world (1,2). Retinal neovascularization is considered an important factor in the pathogenesis of DR (3).…”

Section: Introductionmentioning

confidence: 99%

Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment

Zhao

Peng

et al. 2017

Braz J Med Biol Res

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“…Aldose reductase (AR), best studied as an enzyme of the polyol pathway, is involved in ocular complications of diabetes including diabetic cataract [20–22] and diabetic retinopathy [23, 24]. Recent studies also implicate AR in the pathogenesis of uveitis [25–27] and fibrotic changes associated with posterior capsular opacification [28, 29].…”

Section: Introductionmentioning

confidence: 99%

Aldose reductase mediates retinal microglia activation

Chang

Shieh

Petrash

2016

Biochemical and Biophysical Research Communications

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Retinal microglia (RMG) are one of the major immune cells in charge of surveillance of inflammatory responses in the eye. In the absence of an inflammatory stimulus, RMG reside predominately in the ganglion layer and inner or outer plexiform layers. However, under stress RMG become activated and migrate into the inner nuclear layer (INL) or outer nuclear layer (ONL). Activated RMG in cell culture secrete pro-inflammatory cytokines in a manner sensitive to downregulation by aldose reductase inhibitors. In this study, we utilized CX3CR1GFP mice carrying AR mutant alleles to evaluate the role of AR on RMG activation and migration in vivo. When tested on an ARWT background, IP injection of LPS induced RMG activation and migration into the INL and ONL. However, this phenomenon was largely prevented by AR inhibitors or in AR null mice, or was exacerbated in transgenic mice that over-express AR. LPS-induced increases in ocular levels of TNF-α and CX3CL-1 in WT mice were substantially lower in AR null mice or were reduced by AR inhibitor treatment. These studies demonstrate that AR expression in RMG may contribute to the proinflammatory phenotypes common to various eye diseases such as uveitis and diabetic retinopathy.

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“…Microvascular dysfunction is an important hallmark of DR. Thus, DR is often considered as a microcirculatory disease of retina [2]. Recently, increasing studies have revealed that retinal neurodegeneration is also involved in the pathogenesis of DR, which contributes to the development of microvascular abnormalities [3,4,5].…”

Section: Introductionmentioning

confidence: 99%

Nmnat 1: a Security Guard of Retinal Ganglion Cells (RGCs) in Response to High Glucose Stress

Zhou

Shen

Yao

et al. 2016

Cell Physiol Biochem

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Background/Aims: Retinal neurodegeneration is an early event in the pathological process of diabetic retinopathy (DR). Retinal ganglion cell (RGC) injury is an important pathological feature during neurodegenerative process. Protecting RGCs from high glucose-induced injury is a promising strategy for delaying or hindering diabetes mellitus-related retinal neuropathy. This study aims to investigate the role of Nmnat1, an enzyme which catalyzes a key step in the biosynthesis of nicotinamide adenine dinucleotide (NAD), in high glucose-induced RGC injury. Methods: Western blot and immunofluorescence analysis was conducted to detect Nmnat1 expression pattern in the retina and RGC-5 cell. MTT assay, Hoechst staining, trypan blue staining, and calcein-AM/ propidium iodide (PI) staining was conducted to determine the effect of Nmnat1 knockdown on RGC-5 cell function. Microarray and bioinformatics analysis was conducted to identify potential signaling pathways affected by Nmnat1 knockdown. Pharmacological intervention, molecular intervention, and in vitro experiments were conducted to reveal molecular mechanism of Nmnat1-mediated protective effect on RGC-5 cell function. Results: Nmnat1 is constitutively expressed in retina and RGC-5 cells. Nmnat1 knockdown aggravates RGC injury, and accelerates the development of RGC-5 cell apoptosis upon high glucose stress. MAPK signaling is the primary signaling pathway affected by Nmnat1 knockdown. Under high glucose stress, Nmnat1 knockdown leads to p38-MAPK signaling inactivation. p38-MAPK pathway inhibitor strongly blocks Nmnat1-mediated protective effect on RGC-5 cell function. Conclusion: Nmnat1 protects RGC against high glucose-induced injury via p38-MAPK signaling pathway. Nmnat1 may serve as a neuroprotective target for diabetes mellitus-related retinal neuropathy.

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Update on genetics and diabetic retinopathy

Cited by 35 publications

References 134 publications

Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment

Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment

Aldose reductase mediates retinal microglia activation

Nmnat 1: a Security Guard of Retinal Ganglion Cells (RGCs) in Response to High Glucose Stress

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