Aldose reductase deficiency protects sugar-induced lens opacification in rats

Abstract

Aldose reductase (AKR1B1), which catalyzes the reduction of glucose to sorbitol and lipid aldehydes to lipid alcohols, has been shown to be involved in secondary diabetic complications including cataractogenesis. Rats have high levels of AKR1B1 in lenses and readily develop diabetic cataracts, whereas mice have very low levels of AKR1B1 in their lenses and are not susceptible to hyperglycemic cataracts. Studies with transgenic mice that over-express AKR1B1 indicate that it is the key protein for the development of diabetic complications including diabetic cataract. However, no such studies were performed in genetically altered AKR1B1 rats. Hence, we developed siRNA-based AKR1B1 knockdown rats (ARKO) using the AKR1B1-siRNA-pSuper vector construct. Genotyping analysis suggested that more than 90% of AKR1B1 was knocked down in the littermates. Interestingly, all the male animals were born dead and only 3 female rats survived. Furthermore, all 3 female animals were not able to give birth to F1 generation. Hence, we could not establish an AKR1B1 rat knockdown colony. However, we examined the effect of AKR1B1 knockdown on sugar-induced lens opacification in ex vivo. Our results indicate that rat lenses obtained from AKR1B1 knockdown rats were resistant to high glucose–induced lens opacification as compared to wild-type (WT) rat lenses. Biochemical analysis of lens homogenates showed that the AKR1B1 activity and sorbitol levels were significantly lower in sugar-treated AKR1B1 knockdown rat lenses as compared to WT rat lenses treated with 50 mM glucose. Our results thus confirmed the significance of AKR1B1 in the mediation of sugar-induced lens opacification and indicate the use of AKR1B1 inhibitors in the prevention of cataractogenesis.

Aldose reductase expression as a risk factor for cataract

“…JNK is thought to be a stress-activated protein kinase (SAPK) that can activate apoptosis [18]. Since AR is the rate-limiting step in the polyol pathway [19], inhibitors of AR have become an important topic of research.…”

Syringic Acid Extracted fromHerba dendrobiiPrevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity

“…A complex pathogenic mechanism underlies diabetic cataract. Though the exact mechanism remains uncertain, a large body of research indicates that aldose reductase (AR) is a key enzyme involved in DC development [2]. In order to reduce diabetic cataract incidence and slow the progression of diabetic cataract in current patients, further understanding of the mechanistic involvement of AR in diabetic cataract development and progression is required.…”

Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats

“…However, the rate of conversion of sorbitol to fructose is considerably slow and sorbitol does not diffuse out of the cell, hence resulting in its intracellular accumulation [39]. The role of AR in cataractogenesis is further supported by other studies that observed rodents having low or no AR activity are resistant to development of diabetic cataract [40, 41]. Furthermore, Lee et al [42] demonstrated that cataract development in type 2 diabetes mellitus patient may be influenced by polymorphism in AR gene.…”