Hyperglycemia in the newborn rat induces retinal vascular growth retardation and the recruitment of inflammatory macrophages to the retina

Abstract

Purpose: Ischemic proliferative retinopathies can arise from different underlying pathologies such as retinal vein occlusion, diabetes or prematurity. Recent evidences suggest that transient hyperglycemia in the preterm infant are strongly associated with the occurrence of the ischemic retinopathy. We here evaluate the influence of neonatal hyperglycemia on macrophage recruitment, angiogenesis, and neuronal apoptosis.

Methods: Hyperglycemia was induced in newborn rats by intraperitoneal injection of streptozotocin (STZ) at post natal day one (P1). Animals were grown without insulin treatment and daily monitored for glycemia and weight. Animals were sacrificed on day 3, 6, 14 and 21 for histology, immunohistochemical studies and qPCR quantifications. Retinal vasculature was visualized using an anti-collagen IV antibody and macrophages/microglia were stained using an anti-iba1 antibody.

Results: P1 STZ-injections resulted in a transient increase in glycemia between P3 and P6. Animal survival and weight gain was not affected in animals that had experienced three days of hyperglycemia. Hyperglycemia was associated with (i) a decreased vascular area at P6 (ii) an excessive cell death in the INL and ONL of the posterior pole at P6 leading to a thinning of the posterior retina at P14, (iii) the presence of activated, round-shaped Iba positive cells in the INL and an overall increase in the total number of Iba+ macrophages/microglia cells (iv) and the production of the pro-inflammatory TNFα and IL1β molecules.

Conclusions: Transient hyperglycemia in the newborn retina induced a sustained recruitment of inflammatory macrophages, inhibits physiological angiogenesis, and induces neuronal apoptosis. Production of pro-inflammatory cytokines by macrophages might play an important role in the development of diabetic ischemic retinopathy. Neonatal hyperglycemia induced retinopathy mimics many aspects of retinopathy of prematurity and diabetic retinopathy.

Keywords: 499 diabetic retinopathy • 557 inflammation • 497 development