Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia.
Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia.
复制标题
DOI：
10.3389/fphar.2017.00370
复制
发表时间：
2017
影响因子：
5.6
通讯作者：
Marzocco S
中科院分区：
文献类型：
--
作者：
Adesso S;Magnus T;Cuzzocrea S;Campolo M;Rissiek B;Paciello O;Autore G;Pinto A;Marzocco S
硫酸吲哚酚（IS）是一种蛋白结合的尿毒症毒素，由饮食色氨酸代谢产生，在肾功能受损（如慢性肾病（CKD））患者体内蓄积。IS是一种众所周知的肾血管毒素，但其对中枢神经系统（CNS）细胞的作用却知之甚少。考虑到CKD中CNS合并症领域的兴趣日益增长，我们研究了IS对CNS细胞的影响。在C6星形胶质细胞中，IS（15-60 μM）处理增加了活性氧释放，降低了核因子（红细胞衍生2）样2（Nrf 2）活化以及血红素加氧酶-1（HO-1）和NAD（P）H脱氢酶醌1表达。此外，IS增加芳烃受体（AhR）和核因子-kB（NF-kB）在这些细胞中的激活。在原代小鼠星形胶质细胞和混合神经胶质细胞中进行了类似的观察。IS（15-60 μM）可增加小鼠原代星形胶质细胞和混合胶质细胞中诱导型一氧化氮合酶和环氧合酶-2（考克斯-2）的表达、肿瘤坏死因子-α和白细胞介素-6的释放以及硝基酪氨酸的形成。IS增加了原代胶质细胞AhR和NF-κ B的核转位，减少了Nrf 2的转位和HO-1的表达。此外，IS以剂量依赖性方式诱导神经元细胞死亡。注射IS（800 mg/kg，i. p.）致小鼠脑组织病理学改变，脑组织考克斯-2表达增加，硝基酪氨酸生成增加。总之，我们的研究结果表明，IS在产生神经毒性环境中有显着贡献，它也可能在神经退行性变中发挥潜在作用。IS也可以被认为是CKD相关神经退行性并发症的潜在治疗靶点。
Indoxyl sulfate (IS) is a protein-bound uremic toxin resulting from the metabolism of dietary tryptophan which accumulates in patients with impaired renal function, such as chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15–60 μM) treatment in C6 astrocyte cells increased reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells. Inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, tumor necrosis factor-α and interleukin-6 release and nitrotyrosine formation were increased by IS (15–60 μM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications.