Abstract
Aims/hypothesisCataract surgery in diabetic individuals worsens pre-existing retinopathy and triggers the development of diabetic ocular complications, although the underlying cellular and molecular pathophysiology remains elusive. We hypothesise that lens surgery may exaggerate pre-existing retinal inflammation in diabetes, which may accelerate neurovascular degeneration in diabetic eyes.MethodsMale heterozygous Ins2Akita mice (3 months of age) and C57BL/6 J age-matched siblings received either lens capsulotomy (to mimic human cataract surgery) or corneal incision (sham surgery) in the right eye. At different days post surgery, inflammation in anterior/posterior ocular tissues was assessed by immunohistochemistry and proinflammatory gene expression in the retina by quantitative PCR (qPCR). Degenerative changes in the retina were evaluated by electroretinography, in vivo examination of retinal thickness (using spectral domain optical coherence tomography [SD-OCT]) and morphometric analysis of retinal neurons. The therapeutic benefit of neutralising Wnt/β-catenin signalling following lens capsulotomy was evaluated by intravitreal administration of monoclonal antibody against the co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) (Mab2F1; 5 μg/μl in each eye).ResultsLens capsulotomy triggered the early onset of retinal neurodegeneration in Ins2Akita mice, evidenced by abnormal scotopic a- and b-wave responses, reduced retinal thickness and degeneration of outer/inner retinal neurons. Diabetic Ins2Akita mice also had a higher number of infiltrating ionised calcium-binding adapter molecule 1 (IBA1)/CD68+ cells in the anterior/posterior ocular tissues and increased retinal expression of inflammatory mediators (chemokine [C-C motif] ligand 2 [CCL2] and IL-1β). The expression of β-catenin was significantly increased in the inner nuclear layer, ganglion cells and infiltrating immune cells in Ins2Akita mice receiving capsulotomy. Neutralisation of Wnt/β-catenin signalling by Mab2F1 ameliorated ocular inflammation and prevented capsulotomy-induced retinal degeneration in the Ins2Akita mouse model of diabetes.Conclusions/interpretationTargeting the canonical Wnt/β-catenin signalling pathway may provide a novel approach for the postoperative management of diabetic individuals needing cataract surgery.
Highlights
With an ageing population and the growing prevalence of obesity due to increasingly sedentary lifestyles, the incidence of diabetes mellitus is rising at an alarming rate [1]
We show that lens capsulotomy triggers inflammation in the anterior and posterior eye segments, which is associated with retinal neurodegeneration
We show that capsulotomy-induced ocular inflammation and retinal neurodegeneration is worsened in the diabetic context, as observed in Ins2Akita mice
Summary
With an ageing population and the growing prevalence of obesity due to increasingly sedentary lifestyles, the incidence of diabetes mellitus is rising at an alarming rate [1]. One of the common complications associated with diabetes is diabetic retinopathy, which is the leading cause of vision loss in the working-age population [2]. Diabetic retinopathy is a progressive disorder that results in alterations in the neuroretina, leading to retinal neurodegeneration and microangiopathy in its early stages [3]. Non-proliferative diabetic retinopathy can lead to retinal non-perfusion, which drives pathological intraocular neovascularisation, known as proliferative diabetic retinopathy [4]. How diabetes leads to diabetic retinopathy is still not fully understood; inflammation is known to play an important role in its development and progression [5]. Cataract is the leading cause of blindness worldwide and one of the major factors responsible for vision impairment [7]
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