糖尿病引起的视网膜NAD氧化还原状态变化：药理学调节及其对糖尿病视网膜病变发病机制的影响

Diabetes-induced changes in retinal NAD-redox status: pharmacological modulation and implications for pathogenesis of diabetic retinopathy.

作者信息

Obrosova I G, Stevens M J, Lang H J

机构信息

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, MSRB 11, Room 5570, Ann Arbor, MI 48109-0678, USA.

出版信息

Pharmacology. 2001;62(3):172-80. doi: 10.1159/000056091.

DOI:10.1159/000056091

PMID:11287819

Abstract

Diabetes-induced changes in retinal metabolism and function have been linked to increased aldose reductase activity, hypoxia or 'pseudohypoxia' (increase in NADH/NAD+ attributed to increased sorbitol dehydrogenase activity). To address this controversy, we evaluated the effects of two vasoactive compounds, alpha(1)-adrenoceptor antagonist prazosin and antioxidant DL-alpha-lipoic acid, as well as sorbitol dehydrogenase inhibitor (SDI-157) and aldose reductase inhibitor (sorbinil) on retinal free mitochondrial and cytosolic NAD+/NADH ratios in streptozotocin-diabetic rats. Diabetes-induced decrease in mitochondrial and cytosolic NAD+/NADH ratios was completely or partially corrected by prazosin and DL-alpha-lipoic acid (despite the fact that prazosin did not affect and DL-alpha-lipoic acid even further increased sorbitol pathway activity) as well as by sorbinil, whereas SDI-157 was totally ineffective. Hypoxia-like metabolic changes in the diabetic retina originate from aldose reductase, but not sorbitol dehydrogenase activity.

摘要

糖尿病引起的视网膜代谢和功能变化与醛糖还原酶活性增加、缺氧或“假性缺氧”（由于山梨醇脱氢酶活性增加导致NADH/NAD⁺升高）有关。为了解决这一争议，我们评估了两种血管活性化合物——α(1)-肾上腺素能受体拮抗剂哌唑嗪和抗氧化剂DL-α-硫辛酸，以及山梨醇脱氢酶抑制剂（SDI-157）和醛糖还原酶抑制剂（索比尼尔）对链脲佐菌素诱导的糖尿病大鼠视网膜游离线粒体和胞质NAD⁺/NADH比值的影响。哌唑嗪和DL-α-硫辛酸完全或部分纠正了糖尿病引起的线粒体和胞质NAD⁺/NADH比值降低（尽管哌唑嗪未产生影响，而DL-α-硫辛酸甚至进一步增加了山梨醇途径活性），索比尼尔也有同样效果，而SDI-157则完全无效。糖尿病视网膜中类似缺氧的代谢变化源于醛糖还原酶活性，而非山梨醇脱氢酶活性。