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Leonid Zukin, Michelle Pedler, Biehuoy Shieh, J Mark Petrash; The role of aldose reductase in the development of posterior capsular opacification. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© 2017 Association for Research in Vision and Ophthalmology.
Cataract removal is one of the most common surgeries in the world. Approximately one-fifth of cataract patients will develop a postoperative condition known as posterior capsular opacification (PCO), whereby residual cells in the lens capsule proliferate and obstruct the visual axis. Recent studies have demonstrated that PCO biomarkers can be suppressed through inhibition of aldose reductase (AR), a protein involved with TGFβ-mediated signaling in lens epithelial cells. We hypothesize that inhibition of AR in a mouse model of cataract surgery will prevent the induction of PCO and associated biomarkers, including alpha smooth muscle actin (α-SMA), vimentin (VIM), and fibronectin (FN).
Extracapsular lens extraction was performed on one eye of wild-type C57BL/6, AR-transgenic, and AR knockout mice. Capsules were harvested 5 days post-operatively and PCO biomarker levels, measured by quantitative polymerase chain reaction (q-PCR), were compared between operated and non-operated eyes. In a separate experiment, whole eyes were harvested at 3 and 5 days post-operatively, sectioned (10 μm), and stained with DAPI and α-SMA fluorescent antibodies. To examine pharmacological AR inhibition, analogous surgical procedures were performed on the mice along with 10 mg/kg bid intraperitoneal injections with Sorbinil for 5 days, followed by q-PCR quantification of PCO biomarkers.
As measured by qPCR, genetic knockout of AR suppressed post-operative PCO biomarkers by 66%, 27%, 79% for α-SMA, VIM, and FN, respectively. In contrast, AR overexpression greatly enhanced post-operative markers as evidenced by increases of 430%, 266%, and 359% for α-SMA, VIM, and FN, respectively. Pharmacological AR inhibition with Sorbinil recapitulated these results, with significant biomarker decreases in wild-type (86.99%, 69.95%, and 88.79% decrease in α-SMA, VIM, and FN, respectively) and AR-Tg mice (46.93%, 28.73%, and 43.99% decrease in α-SMA, VIM, and FN, respectively). Immunofluorescent imaging of α-SMA demonstrated development of the aberrant fibrotic process in the different strains.
This study validates the important role of AR in the development of PCO in vivo and presents a promising avenue for further research into the prevention of PCO through AR inhibition.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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