Antagonising Wnt/β-catenin signalling ameliorates lens-capsulotomy-induced retinal degeneration in a mouse model of diabetes

AIMS/HYPOTHESIS: Cataract 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. METHODS: Male heterozygous Ins2(Akita) 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). RESULTS: Lens capsulotomy triggered the early onset of retinal neurodegeneration in Ins2(Akita) mice, evidenced by abnormal scotopic a- and b-wave responses, reduced retinal thickness and degeneration of outer/inner retinal neurons. Diabetic Ins2(Akita) 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 Ins2(Akita) mice receiving capsulotomy. Neutralisation of Wnt/β-catenin signalling by Mab2F1 ameliorated ocular inflammation and prevented capsulotomy-induced retinal degeneration in the Ins2(Akita) mouse model of diabetes. CONCLUSIONS/INTERPRETATION: Targeting the canonical Wnt/β-catenin signalling pathway may provide a novel approach for the postoperative management of diabetic individuals needing cataract surgery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-018-4682-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.