Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells

Chang, Kun-Che; Snow, Anson; LaBarbera, Daniel V.; Petrash, J. Mark

doi:10.1016/j.cbi.2014.10.007

Cited by 43 publications

(37 citation statements)

References 55 publications

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“…Although osmotic stress also resulted in an increase in oxidative stress, it did not reach significant levels. This may be mediated, in part, through uptake of D-glucose, but not L-glucose, by RPE cells and enhanced aldose reductase activity (13). However, the increased oxidative stress in RPE cells was not associated with changes in oxidative response genes, including NRF2 and its downstream effectors HO-1 and Prdx2.…”

Section: Discussionmentioning

confidence: 88%

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

Farnoodian

Halbach

Slinger

et al. 2016

American Journal of Physiology-Cell Physiology

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Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis.

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Section: Discussionmentioning

confidence: 88%

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

Farnoodian

Halbach

Slinger

et al. 2016

American Journal of Physiology-Cell Physiology

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“…10 A positive correlation between hyperglycemia and AR expression has been observed in many studies 11,12 and shows that AR activation plays a key role in diabetic cataract (DC) formation. 13,14 Indeed, diabetes-dependent increases in AR activity can be found in lenses of a rat model of diabetic cataract.…”

mentioning

confidence: 87%

“…23,24 Our previous studies indicated that genetic ablation or pharmacological inhibition of AR reduced inflammatory responses in the eye 20,21 and prevented retinal pigment epithelial (RPE) cell death under hyperglycemic conditions. 11 As a result of these observations, blockade of AR appears to be a strategy for prevention of a variety of ocular diseases. Unfortunately, previous clinical trials of ARIs have been unsuccessful due to toxicity and side effects related to poor specificity.…”

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confidence: 99%

Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract

Chang

Sanborn

et al. 2016

J. Nat. Prod.

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Aldose reductase (AR) in the lens plays an important role in the pathogenesis of diabetic cataract (DC) by contributing to osmotic and oxidative stress associated with accelerated glucose metabolism through the polyol pathway. Therefore, inhibition of AR in the lens may hold the key to prevent DC formation. Emodin, a bioactive compound isolated from plants, has been implicated as a therapy for diabetes. However, its inhibitory activity against AR remains unclear. Our results showed that emodin has good selectively inhibitory activity against AR (IC50 = 2.69 ± 0.90 μM) but not other aldo-keto reductases and is stable at 37 °C for at least 7 days. Enzyme kinetic studies demonstrated an uncompetitive inhibition against AR with a corresponding inhibition constant of 2.113 ± 0.095 μM. In in vivo studies, oral administration of emodin reduced the incidence and severity of morphological markers of cataract in lenses of AR transgenic mice. Computational modeling of the AR–NADP–emodin ternary complex indicated that the 3-hydroxy group of emodin plays an essential role by interacting with Ser302 through hydrogen bonding in the specificity pocket of AR. All the findings above provide encouraging evidence for emodin as a potential therapeutic agent to prevent cataract in diabetic patients.

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“…Recent studies also implicate AR in the pathogenesis of uveitis [25–27] and fibrotic changes associated with posterior capsular opacification [28, 29]. Genetic or pharmacological blockade of AR successfully alleviates inflammatory responses induced by endotoxin [25, 26, 30–32] or hyperglycemia [33–35]. Our previous study showed that genetic or pharmacological downregulation of AR prevents endotoxin-induced inflammatory responses in RMG primary cell cultures [26].…”

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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Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells

Cited by 43 publications

References 55 publications

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

Characterization of Emodin as a Therapeutic Agent for Diabetic Cataract

Aldose reductase mediates retinal microglia activation

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