Ghahary A, Chakrabarti S, Sima A A, Murphy L J
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Diabetes. 1991 Nov;40(11):1391-6. doi: 10.2337/diab.40.11.1391.
Tissue accumulation of sorbitol secondary to enhanced polyol-pathway activity is believed to play an important role in the development of diabetic complications. We previously demonstrated sorbitol accumulation, due in part to enhanced expression of aldose reductase (AR) in the diabetic kidney. In this study, we quantitated AR enzyme activity, immunoreactivity, and mRNA in various tissues from nondiabetic and diabetic BB/Wor rats 3 mo after onset of diabetes. In addition, the effects of intensive insulin treatment (3-6 U/day) and the effects of the AR inhibitor Statil (25 mg.kg-1.day-1) on AR expression were determined. Of 13 tissues examined, AR activity was significantly increased in the lens, kidney, sciatic nerve, skeletal muscle, retina, and spinal cord from diabetic rats compared with age-matched nondiabetic control rats. In most tissues, AR immunoreactivity and AR mRNA were proportionately elevated. Intensive insulin treatment, which normalized blood glucose and glycosylated hemoglobin, significantly reduced AR activity and immunoreactivity. AR mRNA abundance was also reduced in tissues from insulin-treated diabetic rats. Statil treatment had no significant effect on AR immunoreactivity or AR mRNA abundance, although AR activity in tissues from Statil-treated diabetic rats was significantly reduced compared with untreated diabetic rats. These studies demonstrate that the expression of the AR gene is upregulated in most tissues of the diabetic rat, that insulin treatment reverses this phenomenon, and that AR inhibition has no effect on AR gene expression.
继发于多元醇途径活性增强的山梨醇组织蓄积被认为在糖尿病并发症的发生发展中起重要作用。我们先前已证明糖尿病肾脏中山梨醇蓄积，部分原因是醛糖还原酶（AR）表达增强。在本研究中，我们对糖尿病发病3个月后的非糖尿病和糖尿病BB/Wor大鼠的各种组织中的AR酶活性、免疫反应性和mRNA进行了定量分析。此外，还确定了强化胰岛素治疗（3 - 6 U/天）和AR抑制剂Statil（25 mg·kg⁻¹·天⁻¹）对AR表达的影响。在所检测的13种组织中，与年龄匹配的非糖尿病对照大鼠相比，糖尿病大鼠的晶状体、肾脏、坐骨神经、骨骼肌、视网膜和脊髓中的AR活性显著增加。在大多数组织中，AR免疫反应性和AR mRNA成比例升高。使血糖和糖化血红蛋白正常化的强化胰岛素治疗显著降低了AR活性和免疫反应性。胰岛素治疗的糖尿病大鼠组织中的AR mRNA丰度也降低。Statil治疗对AR免疫反应性或AR mRNA丰度没有显著影响，尽管与未治疗的糖尿病大鼠相比，Statil治疗的糖尿病大鼠组织中的AR活性显著降低。这些研究表明，糖尿病大鼠的大多数组织中AR基因表达上调，胰岛素治疗可逆转这一现象，而AR抑制对AR基因表达没有影响。
