Long-Term Administration of the Histone Deacetylase Inhibitor Vorinostat Attenuates Renal Injury in Experimental Diabetes through an Endothelial Nitric Oxide Synthase-Dependent Mechanism
Long-Term Administration of the Histone Deacetylase Inhibitor Vorinostat Attenuates Renal Injury in Experimental Diabetes through an Endothelial Nitric Oxide Synthase-Dependent Mechanism
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DOI：
10.1016/j.ajpath.2011.01.044
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发表时间：
2011-05-01
影响因子：
6
通讯作者：
Gilbert, Richard E.
中科院分区：
文献类型：
--
作者：
Advani, Andrew;Huang, Qingling;Gilbert, Richard E.
基因表达的表观遗传变化在糖尿病并发症的发展中发挥了作用，包括肾病。组蛋白脱乙酰酶(HDAC)是一组通过改变组蛋白和非组蛋白的乙酰化状态而发挥表观遗传效应的酶。在本研究中，我们研究了临床上可用的HDAC抑制剂伏立恒在糖尿病肾病小鼠模型中的作用，目的如下：确定其在糖尿病肾病进展中的作用，并通过调节内皮型一氧化氮合酶(ENOS)的表达来探讨其作用机制。对照组、链脲佐菌素糖尿病野生型和eNOS(-/-)小鼠每天口服伏立诺，连续18周。在不影响血糖浓度或血压的情况下，威立诺特减少了链脲佐菌素野生型小鼠的蛋白尿、系膜IV型胶原沉积和氧化-亚硝化应激。这些减弱作用与eNOS在小鼠肾脏和培养的人脐静脉内皮细胞中的表达减少50%有关。在eNOS基因缺陷的糖尿病小鼠中，伏立诺治疗对蛋白尿、肾小球IV型胶原浓度或系膜溶解没有影响。这些观察结果说明了长期抑制HDAC对糖尿病肾病的治疗效果，并强调了eNOS活性和氧化应激之间相互作用在介导这些效应中的重要性。(AMJ Pathol2011,178：2205-2214；doi：10.1016/j.ajpath.2011.01.044)
Epigenetic changes in gene expression play a role in the development of diabetic complications, including nephropathy. Histone deacetylases (HDACs) are a group of enzymes that exert epigenetic effects by altering the acetylation status of histone and nonhistone proteins. In the current study, we investigated the action of the clinically available HDAC inhibitor vorinostat in a mouse model of diabetic nephropathy, with the following aims: to define its effect on the progression of renal injury and to explore its mechanism of action by focusing on its role in regulating the expression of endothelial nitric oxide synthase (eNOS). Control and streptozotocin-diabetic wild-type and eNOS(-/-) mice were treated with vorinostat by daily oral dosing for 18 weeks. Without affecting either blood glucose concentration or blood pressure, vorinostat decreased albuminuria, mesangial collagen IV deposition, and oxidative-nitrosative stress in streptozotocin-wild-type mice. These attenuating effects were associated with a >50% reduction in eNOS expression in mouse kidneys and in cultured human umbilical vein endothelial cells. Vorinostat treatment had no effect on albuminuria, glomerular collagen IV concentration, or mesangiolysis in diabetic mice genetically deficient in eNOS. These observations illustrate the therapeutic efficacy of long-term HDAC inhibition in diabetic nephropathy and emphasize the importance of the interplay between eNOS activity and oxidative stress in mediating these effects. (AmJ Pathol 2011, 178: 2205-2214; DOI: 10.1016/j.ajpath.2011.01.044)