聚（ADP-核糖）聚合酶-1 抑制剂 1,5-异喹啉二醇可减轻糖尿病诱导的视网膜 NADPH 氧化酶衍生的氧化应激。
The Poly(ADP-Ribose)Polymerase-1 Inhibitor 1,5-Isoquinolinediol Attenuate Diabetes-Induced NADPH Oxidase-Derived Oxidative Stress in Retina.
机构信息
1 Department of Ophthalmology, College of Medicine, King Saud University , Riyadh, Saudi Arabia .
2 Dr. Nasser Al-Rashid Research Chair in Ophthalmology , Riyadh, Saudi Arabia .
出版信息
J Ocul Pharmacol Ther. 2018 Sep;34(7):512-520. doi: 10.1089/jop.2017.0117. Epub 2018 Jun 18.
PURPOSE
To examine the effects of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor 1,5-isoquinolinediol (IQ) on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived oxidative stress in diabetic retina.
METHODS
Streptozotocin-induced diabetic rats were treated with IQ. The NADPH oxidase enzyme activity was determined by luminometer. Expression of gp, P and nitrated proteins was examined by western blot. Interaction between gp and P was determined by coimmunoprecipitation. Enzyme-linked immunosorbent assay was utilized to measure the level of retinal total antioxidant capacity. We also studied the effect of the IQ on hydrogen peroxide (HO)-induced cleavage of PARP-1 and caspase-3 in human retinal Müller glial cells.
RESULTS
Treatment of retinal Müller cells with HO-induced PARP-1 and caspase-3 cleavage that was attenuated by IQ cotreatment. Diabetes upregulated PARP-1, NADPH oxidase enzyme activity, gp, P, nitrated protein expression and interaction between gp and P, and downregulated total antioxidant capacity in the retinas compared with nondiabetic rats. Administration of IQ did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of NADPH oxidase enzyme activity and expressions of gp, P, and nitrated proteins and interaction between gp and P. In addition, IQ ameliorated diabetes-induced downregulation of total antioxidant capacity in the retina.
CONCLUSION
PARP-1 inhibition by IQ protects diabetic retina from NADPH oxidase-derived oxidative stress. Thus, inhibition of PARP-1 could have potential therapeutic value in preventing the development of diabetic retinopathy.
目的
研究聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂 1,5-异喹啉二醇（IQ）对糖尿病视网膜 NADPH 氧化酶衍生的氧化应激的影响。
方法
用 IQ 处理链脲佐菌素诱导的糖尿病大鼠。通过发光计测定 NADPH 氧化酶酶活性。通过 Western blot 检测 gp、P 和硝化蛋白的表达。通过共免疫沉淀测定 gp 和 P 之间的相互作用。酶联免疫吸附试验用于测量视网膜总抗氧化能力的水平。我们还研究了 IQ 对人视网膜 Müller 胶质细胞中 HO 诱导的 PARP-1 和 caspase-3 裂解的影响。
结果
HO 诱导的视网膜 Müller 细胞中 PARP-1 和 caspase-3 裂解，用 IQ 共同处理可减弱这种裂解。与非糖尿病大鼠相比，糖尿病使视网膜中 PARP-1、NADPH 氧化酶酶活性、gp、P、硝化蛋白表达和 gp 与 P 之间的相互作用增加，而总抗氧化能力降低。给予 IQ 不会影响糖尿病大鼠的代谢状态，但可显著减弱糖尿病诱导的 NADPH 氧化酶酶活性和 gp、P 和硝化蛋白表达以及 gp 与 P 之间相互作用的上调。此外，IQ 改善了糖尿病诱导的视网膜总抗氧化能力的下调。
结论
IQ 通过抑制 PARP-1 来保护糖尿病视网膜免受 NADPH 氧化酶衍生的氧化应激。因此，PARP-1 的抑制可能在预防糖尿病性视网膜病变的发展方面具有潜在的治疗价值。
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