Aldose reductase inhibition enhances lens regeneration in mice

Abstract

After cataract surgery, epithelial cells lining the anterior lens capsule can transition to one of two divergent pathways, including fibrosis which leads to posterior capsular opacification (PCO), or lens fiber cell differentiation which leads to regeneration of lens material. We previously showed that the PCO response can be suppressed with aldose reductase (AR) inhibitors. In this present study we show that AR inhibition, both genetic and pharmacologic with Sorbinil, can augment the process of lens regeneration. Extracapsular lens extraction (ECLE) was carried out in C57BL/6 (WT), AR overexpression (AR-Tg), and AR knockout (ARKO) mice, and in some cases in mice treated with the AR inhibitor sorbinil. Whole eyes were harvested approximately 8 weeks after ECLE and evaluated by histological analysis and immunostaining for the fiber cell marker γcrystallin. All eyes examined for lens regeneration were paraffin embedded for serial sectioning to produce three-dimensional reconstructed models of lens morphology and size. We observed that AR-null mice respond to ECLE by regenerating a lens-like structure with a circular shape and array of cell nuclei reminiscent of the lens bow region typical of the native mammalian lens. Although WT and AR-Tg eyes also produced some regenerated lens material after ECLE, their structures were consistently smaller than ARKO regenerated lenses. WT mice treated with sorbinil showed higher levels of lens regeneration after ECLE compared to WT mice, as assessed by size and three-dimensional morphology. Altogether, this study adds evidence for a critical role for AR in the response of lens epithelial cells to cataract extraction and lens regeneration.

Three-dimensional data capture and analysis of intact eye lenses evidences emmetropia-associated changes in epithelial cell organization

“…It confirms the previously reported age-dependent changes in cell density, particularly those in the GZ and MR of the epithelium of lenses taken from C57/BL6J mice. The method reduces time and resources needed for analysis, and eliminates data distortion encountered in previous methods such as flat mounting the epithelium 25 – 27 , which is a problem for small, round animal lenses such as those in the mouse eye 11 , and serially sectioning the lens 28 , 29 or physically restraining with potential to deform lens shape 18 . Moreover, the algorithm independently calculates the position of the anterior pole and delivers cell density measurements using a three-dimensional polar coordinate system to position every cell in both xyz and spherical angle format.…”

Posterior capsule opacification: What's in the bag?

“…In vivo PCO animal model studies report the presence of Soemmerring's ring (Lois et al, 2003;Zukin et al, 2019;Zukin et al, 2018). At present, these models have not been fully exploited to understand the mechanisms driving Soemmerring's ring formation, but a recent study has suggested that aldose reductase inhibition could promote its formation (Zukin et al, 2019). Moreover, in the rat, electrical fields play an important role in lens regeneration (Lois et al, 2010) following fibre cell removal.…”

“…Therefore, it is important to consider the impact on matrix contraction, rather than solely concentrating on EMT, when developing and evaluating anti-TGFβ/fibrotic strategies to manage PCO. Furthermore, the ability of aldose reductase inhibition on PCO formation was recently assessed (Zukin et al, 2019;Zukin et al, 2018). In a mouse model of PCO, genetic and chemical inhibition of aldose reductase could suppress surgical induced events associated with fibrotic PCO (Zukin et al, 2018), however Soemmerring's ring formation was enhanced (Zukin et al, 2019).…”

Research Progress of Drug Prophylaxis for Lens Capsule Opacification after Cataract Surgery

“…Both studies showed that AR inhibitor Sorbinil might contribute to preventing capsule opacification via blocking MAPK signaling pathway, which could inhibit LECs' proliferation and EMT simultaneously. However, a novel study [31] found that Sorbinil has the ability of promoting lens regeneration, another process that happened with EMT of LECs after cataract surgery, which may weaken the possible function of AR inhibitor Sorbinil in preventing lens capsule opacification.…”