Genetic Inactivation of Aldose Reductase does not prevent ERG deficits associated with STZ-induced Diabetes

Abstract

Purpose: : We have previously reported (ARVO 2011) that streptozotocin (STZ)-induced diabetes elicits reductions in the amplitude of specific components of both the dc- and standard ERG waveforms. Aldose reductase (AR) is the first enzyme required in the polyol-mediated metabolism of glucose, and others have reported that AR inhibitors improve diabetes-induced ERG defects. Here, we used control and AR^-/- mice to determine if genetic inactivation of this enzyme prevents retinal electrophysiologic defects observed in a mouse model of type 1 diabetes.

Methods: : All mice studied (WT or AR^-/-) were of the C57BL/6J strain. STZ was used to induce hyperglycemia and type 1 diabetes. Diabetic and age-matched non-diabetic controls of each genotype were maintained for 22 weeks; diabetics were treated with suboptimal doses of insulin to prevent body weight loss but not prevent hyperglycemia. ERG-based techniques were used to measure the light-evoked components of the RPE (dc-ERG) and the neural retina (a-wave, b-wave).

Results: : In comparison to non-diabetic controls, both WT and AR^-/- diabetic mice displayed significant decreases in the c-wave (WT=1.18; AR^-/- =1.36; WTdiab=0.64; AR^-/-diab=0.56 mV), fast oscillation (WT=1.43; AR^-/- =1.62; WTdiab=0.87; AR^-/-diab=0.75 mV), and off response (WT= -0.73; AR^-/- = -0.83; WTdiab= -0.32; AR^-/-diab= -0.33 mV) of the dc-ERG. Non-diabetic AR^-/- mice displayed larger ERG component amplitudes than did non-diabetic WT mice, however, the amplitude of dc-ERG components in diabetic AR^-/- animals were similar to WT diabetics. ERG a-wave amplitudes were not reduced in either diabetic group (e.g. in response to 1.38 log (cd s/m²): WT=313.4; AR^-/- =379.3; WTdiab=310.8; AR^-/-diab=329.5 μV), but b-wave amplitudes were modestly lower in WT and AR^-/- diabetic mice (e.g. in response to 1.38 log (cd s/m²): WT=576.3; AR^-/- =740.1; WTdiab=479.2; AR^-/-diab=518.6 μV).

Conclusions: : Electrophysiologic evaluation shows that function of the RPE and retina are disrupted in the STZ-induced mouse model of type 1 diabetes, and these defects are not ameliorated by deletion of AR. This finding suggests that benefits observed in the ERG following pharmacological inhibition of AR were secondary to off-target effects of the drugs.

Keywords: diabetes • electroretinography: non-clinical