Glucose exposure suppresses brain aromatase and impairs retinal regeneration in zebrafish.

Abstract

Zebrafish possess a unique capacity for retinal regeneration mediated by Müller glia (MG), in which the estrogen-synthesizing enzyme aromatase B (AroB, encoded by cyp19a1b) plays an important regulatory role. In this study, we investigated the impact of chronic glucose exposure on MG-driven retinal regeneration following mechanical injury. We found that AroB was expressed across multiple retinal layers, including the ganglion cell layer (GCL), inner nuclear layer (INL), outer nuclear layer (ONL), and both plexiform layers. Within the INL AroB colocalized with glutamine synthetase (GS)MG in controls, but was significantly suppressed in retinas exposed to 3 % glucose, a reduction corroborated by Western blot analysis, qRT-PCR, and measurements of Elevels. Retinal injury induced an upregulation of AroB and GS expression and triggered robust MG proliferation in controls, as indicated by EdU incorporation. In contrast, glucose exposure reduced the number of EdUproliferating cells, and colocalization of AroB/MGwith EdUnuclei was absent in the injured glucose-treated group. BrdU labeling performed 3 h before sacrifice revealed ongoing proliferation that followed a similar pattern to EdU, except that BrdUcells in glucose-exposed injured retinas eventually reached levels comparable to injured controls, suggesting a delay in regenerative proliferation. TUNEL staining showed significantly higher numbers of apoptotic cells in injured glucose-exposed retinas compared with injured controls, while no differences were detected between uninjured groups. Together, these findings demonstrate that chronic glucose exposure suppresses AroB expression, impairs early MG activation, delays regenerative proliferation, and exacerbates cell death after retinal injury, highlighting a potential mechanism by which hyperglycemia compromises endogenous retinal repair and contributes to diabetic retinopathy (DR). Nonetheless, given humans' limited regenerative capacity, these mechanisms may not directly translate but still reveal pathways that could aid retinal repair in mammals.