Prevention of Posterior Capsular Opacification through Aldose Reductase Inhibition

Yadav, Umesh C.S.; Ighani-Hosseinabad, F.; Kuijk, Frederik J.G.M. van; Srivastava, Satish K.; Ramana, Kota V.

doi:10.1167/iovs.08-2322

Cited by 31 publications

(35 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies from our lab and those from Ramana and Srivastava have shown that AR inhibition attenuates cell proliferation, cell migration and EMT process on LECs [9, 32]. In this study, we investigated different level of AR expression on primary LECs.…”

Section: Discussionmentioning

confidence: 97%

Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells

Chang

Shieh

Petrash

2017

Chemico-Biological Interactions

View full text Add to dashboard Cite

Cataract is the most frequent cause of blindness worldwide and is treated by surgical removal of the opaque lens to restore the light path to the retina. While cataract surgery is a safe procedure, some patients develop a complication of the surgery involving opacification and wrinkling of the posterior lens capsule. This process, called posterior capsule opacification (PCO), requires a second clinical treatment that can in turn lead to additional complications. Prevention of PCO is a current unmet need in the vision care enterprise. The pathogenesis of PCO involves the transition of lens epithelial cells to a mesenchymal phenotype, designated epithelial-to-mesenchymal transition (EMT). Our previous studies showed that transgenic mice designed for overexpression of human aldose reductase developed lens defects reminiscent of PCO. In the current study, we evaluated the impact of aldose reductase (AR) on expression of expression of EMT markers in the lens. Primary lens epithelial cells from AR-transgenic mice showed downregulated expression of Foxe3 and Pax6 and increased expression of α-SMA, fibronectin and snail, a pattern of gene expression typical of cells undergoing EMT. A role for AR in these changes was further confirmed when we observed that they could be normalized by treatment of cells with Sorbinil, an AR inhibitor. Smad-dependent and Smad-independent pathways are known to contribute to EMT. Interestingly, AR overexpression induced ERK but not Smad-2 activation. These results suggest that elevation of AR may lead to activation of ERK signaling and thus play a role in TGF-β/Smad independent induction of EMT in lens epithelial cells.

show abstract

Section: Discussionmentioning

confidence: 97%

Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells

Chang

Shieh

Petrash

2017

Chemico-Biological Interactions

View full text Add to dashboard Cite

show abstract

“…In addition, aberration in integrin‐mediated cell anchoring has also been implicated in lens epithelial cell EMT (Mamuya et al ., 2014). Recent studies have also shown a role for aldose reductase, MMP, microRNA, and histone deacetylases in lens epithelial cell EMT (Yadav et al ., 2009; Wang et al ., 2013; Korol et al ., 2014; Xie et al ., 2014). …”

Section: Introductionmentioning

confidence: 99%

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

et al. 2016

View full text Add to dashboard Cite

SummaryProteins in basement membrane (BM) are long‐lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial‐to‐mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age‐dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC‐MS/MS. The TGFβ2‐mediated upregulation of the mRNA levels (by qPCR) of EMT‐associated proteins was significantly enhanced in cells cultured on AGE‐modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2‐mediated α‐smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2‐mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes‐associated fibrosis.

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

Aldose reductase mediates retinal microglia activation

Chang

Shieh

Petrash

2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

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.

show abstract

Prevention of Posterior Capsular Opacification through Aldose Reductase Inhibition

Cited by 31 publications

References 38 publications

Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells

Influence of aldose reductase on epithelial-to-mesenchymal transition signaling in lens epithelial cells

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

Aldose reductase mediates retinal microglia activation

Contact Info

Product

Resources

About