Abstract
ABSTRACTProlonged hyperglycemia can alter retinal function, ultimately resulting in blindness. Adult zebrafish adults exposed to alternating conditions of 2% glucose/0% glucose display a 3× increase in blood sugar levels. After 4 weeks of treatment, electroretinograms (ERGs) were recorded from isolated, perfused, in vitro eyecups. Control animals were exposed to alternating 2% mannitol/0% mannitol (osmotic control) or to alternating water (0% glucose/0% glucose; handling control). Two types of ERGs were recorded: (1) native ERGs measured using white-light stimuli and medium without synaptic blockers; and (2) spectral ERGs measured with an AMPA/kainate receptor antagonist, isolating photoreceptor-to-ON-bipolar-cell synapses, and a spectral protocol that separated red (R), green (G), blue (B) and UV cone signals. Retinas were evaluated for changes in layer thickness and for the inflammatory markers GFAP and Nf-κB (RelA or p65). In native ERGs, hyperglycemic b- and d-waves were lower in amplitude than the b- and d-waves of mannitol controls. Alteration of waveshape became severe, with b-waves becoming more transient and ERG responses showing more PIII-like (a-wave) characteristics. For spectral ERGs, waveshape appeared similar in all treatment groups. However, a1- and b2-wave implicit times were significantly longer, and amplitudes were significantly reduced, in response to hyperglycemic treatment, owing to the functional reduction in signals from R, G and B cones. Nf-κB increased significantly in hyperglycemic retinas, but the increase in GFAP was not significant and retinal layer thickness was unaffected. Thus, prolonged hyperglycemia triggers an inflammatory response and functional deficits localized to specific cone types, indicating the rapid onset of neural complications in the zebrafish model of diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is a leading cause of blindness and visual impairment in the United States
As previously reported (Nelson and Singla, 2009), light stimulation of isolated zebrafish eyecups superfused in medium containing an AMPA/KA receptor antagonist resulted in a negative-going wave, the a1 component of the a-wave, immediately after light ON, followed by a large, positive wave, the b2 component of the b-wave
Blood sugar and wet weight measurements Blood sugar measurements of fish alternately exposed to 2% glucose solution/0% glucose solution averaged 135±36.7 mg/dL after 28 days of treatment, a significant increase compared with values from mannitol-treated (n=8) and water-treated (n=6) controls (Table 1A; one-way analysis of variance (ANOVA), P=0.011)
Summary
Diabetic retinopathy (DR) is a leading cause of blindness and visual impairment in the United States (nei.nih.gov/health/diabetic). Received 24 April 2018; Accepted 22 August 2018 complications in DR are believed to be caused by prolonged high levels of glucose (hyperglycemia) that increase inflammatory mediators (Kern, 2007; Romeo et al, 2002) and vascular permeability (Guthrie and Guthrie, 2004). Increased permeability stimulates the formation of new, fragile vessels that can subsequently rupture. The resulting hemorrhage and ischemia damages retinal nerve cells, resulting in vision loss
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