Lysyl oxidase inhibition prevents inflammation-dependent retinal vascular atrophy in early diabetic retinopathy

Abstract

Purpose : Retinal vascular inflammation is implicated in the development of vascular lesions of early diabetic retinopathy (DR). Our previous in vitro work identified lysyl oxidase (LOX)-mediated retinal vascular stiffening as an independent mediator of endothelial ICAM-1 upregulation, a key factor in diabetes-associated retinal inflammation. Using an experimental mouse model of early DR, here we examine the degree to which chemically inhibiting LOX blocks retinal inflammation and downstream vascular and vision defects in diabetic retina.

Methods : Male (8-10 weeks old) C57BL/6 mice were divided into three groups (n= 25/group) viz. non diabetic (ND), streptozotocin-induced diabetic (D), and diabetic + LOX inhibitor beta-aminopropionitrile (3 mg/kg drinking water) (D+BAPN). After 30 weeks of diabetes, superoxide production was measured by the lucigenin method while capillary degeneration was assessed on the retinal vessels isolated using the elastase digest method, followed by Periodic acid-Schiff staining. Vascular leakage was determined in retinal cross-sections following intravenous FITC-albumin injection and fluorometric quantification of its leakage into retinal neural tissue. Visual acuity and contrast sensitivity were assessed by virtual optokinetic test. Ongoing experiments include measurements of a) inflammatory markers at gene and protein levels, b) retinal capillary stiffness by atomic force microscopy, and c) retinal photoreceptor and ganglion cell viability.

Results : When compared with ND group, D group exhibited a significant increase (p=0.001) in retinal superoxide production, which was significantly decreased in D+BAPN group (p<0.05). Similarly, the capillary degeneration that developed in D group (p<0.0001 vs ND) was significantly reduced in D+BAPN group (p<0.05 vs D controls). However, neither the diabetes-induced increase in retinal capillary permeability nor the reduction in visual acuity were significantly inhibited in D+BAPN group (both p<0.01 compared to ND). Nevertheless, the loss in contrast sensitivity seen in D group was markedly prevented in D+BAPN group.

Conclusions : LOX inhibition significantly suppressed the diabetes-induced increase in retinal superoxide and vascular atrophy while minimizing the loss in contrast sensitivity. However, LOX inhibition did not exert any significant protective effect on vascular hyperpermeability and impaired visual acuity.

This is a 2020 ARVO Annual Meeting abstract.