Diabetes-Independent Retinal Phenotypes in an Aldose Reductase Transgenic Mouse Model

Abstract

Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, has been implicated in the onset and development of the ocular complications of diabetes, including cataracts and retinopathy. Despite decades of research conducted to address possible mechanisms, questions still persist in understanding if or how AR contributes to imbalances leading to diabetic eye disease. To address these questions, we created a strain of transgenic mice engineered for the overexpression of human AR (AR-Tg). In the course of monitoring these animals for age-related retinal phenotypes, we observed signs of Müller cell gliosis characterized by strong immunostaining for glial fibrillary acidic protein. In addition, we observed increased staining for Iba1, consistent with an increase in the number of retinal microglia, a marker of retinal inflammation. Compared to age-matched nontransgenic controls, AR-Tg mice showed an age-dependent loss of Brn3a-positive retinal ganglion cells and an associated decrease in PERG amplitude. Both RGC-related phenotypes were rescued in animals treated with Sorbinil in drinking water. These results support the hypothesis that increased levels of AR may be a risk factor for structural and functional changes known to accompany retinopathy in humans.

Aldose reductase inhibition decelerates optic nerve degeneration by alleviating retinal microglia activation

“…We observe that Sorbinil treatment plays a role in delaying distal axonal degeneration one week after ONC. Our results further corroborate a recent study showing that AR overexpression transgenic mice significantly lose their RGCs, which could be rescued by AR inhibition 78 .…”

The Role of Aldose Reductase in Beta-Amyloid-Induced Microglia Activation

“…The AR polyol pathway induces inflammation by activating ROS production as well as NF-κB and p38/MAPK signaling [ 22 , 24 , 37 , 38 , 39 , 40 ]. In the eyes, AR inhibition alleviates endotoxin-induced microglia activation in the retina [ 17 , 32 , 41 ] and AR overexpression leads to RGC loss [ 18 ]. We next ask whether results taken from RGCs can be extrapolated to the rest of the brain/CNS.…”

“…In contrast, increased AR in transgenic mice increases microglia migration into the inner and outer nuclear layers of the retina [ 17 ]. Another study showed that activated microglia infiltrated into the retina of transgenic mice overexpressing AR, resulting in retinal ganglion cell (RGC) loss [ 18 ]. Because AR plays a critical role in microglia activation and retinal neurodegeneration, we asked whether AR also regulates β-amyloid-induced microglial activation.…”

Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance

“…Thus. to determine the importance of AR and the polyol pathway in glucose-dependent growth retardation in aldolase B KO mice, we decided to test the efficiency of sorbinil, a well-characterized AR inhibitor [15,16]. To this end, we first exposed aldolase B KO mice to 0% control or 15% glucose solutions for 6 weeks, and then animals were subsequently divided into the same glucose solutions containing either vehicle or sorbinil (0.25 mg/mL) for another 6 weeks (Figure 2H, left).…”