Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB.
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DOI：
10.1186/1471-2369-14-56
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发表时间：
2013-03-04
期刊：
影响因子：
2.3
通讯作者：
Niwa T
中科院分区：
文献类型：
--
作者：
Bolati D;Shimizu H;Yisireyili M;Nishijima F;Niwa T
硫酸吲哚酚是一种尿毒症毒素，在慢性肾病（CKD）患者的血清中蓄积，加速CKD的进展。在CKD大鼠肾脏中，核因子（红细胞衍生2）样2（Nrf 2）及其相关基因的表达下调。AST-120是一种口服吸附剂，可降低血清硫酸吲哚酚并减缓CKD的进展。本研究旨在确定硫酸吲哚酚是否下调人近端肾小管细胞和大鼠肾脏中的Nrf 2表达，以及AST-120是否上调CKD大鼠肾脏中的Nrf 2表达。使用作为人近端肾小管细胞的HK-2细胞和以下动物，测定硫酸吲哚酚对Nrf 2表达的影响：（1）Dahl盐抗性正常血压大鼠（DN），（2）Dahl盐抗性正常血压硫酸吲哚酚给药大鼠（DN+IS），（3）Dahl盐敏感性高血压大鼠（DH），和（4）Dahl盐敏感性高血压硫酸吲哚酚给药大鼠（DH+IS）。此外，将AST-120给予肾次全切除的CKD大鼠，以确定其对Nrf 2表达的影响。硫酸吲哚酚下调HK-2细胞Nrf 2表达。核因子-κB（NF-κB）抑制剂（吡咯烷二硫代氨基甲酸酯）和NF-κB p65特异性小干扰RNA可缓解硫酸吲哚酚诱导的Nrf 2表达下调。与DN相比，DN+IS、DH和DH+IS大鼠肾脏Nrf 2及其下游靶基因血红素加氧酶-1（HO-1）和NAD（P）H：醌氧化还原酶1（NQO 1）的表达降低，肾脏活性氧（ROS）标志物8-羟基脱氧鸟苷（8-OHdG）的表达增加。因此，硫酸吲哚酚，以及高血压，下调大鼠肾脏Nrf 2的表达。与对照组相比，AST-120可上调肾脏Nrf 2、HO-1和NQO 1的表达，抑制肾脏8-OHdG的表达。硫酸吲哚酚通过激活NF-κB下调肾脏Nrf 2的表达，随后下调HO-1和NQO 1并增加ROS的产生。此外，AST-120通过清除血清硫酸吲哚酚上调CKD大鼠肾脏Nrf 2的表达，随后上调HO-1和NQO 1并减少ROS的产生。
Indoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. In CKD rat kidney, the expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its related genes are downregulated. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. The present study aimed to determine whether indoxyl sulfate downregulates Nrf2 expression in human proximal tubular cells and rat kidneys and whether AST-120 upregulates Nrf2 expression in CKD rat kidneys. Effects of indoxyl sulfate on expression of Nrf2 were determined using HK-2 cells as human proximal tubular cells and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). Further, AST-120 was administered to subtotally nephrectomized CKD rats to determine its effect on the expression of Nrf2. Indoxyl sulfate downregulated Nrf2 expression in HK-2 cells. The indoxyl sulfate-induced downregulation of Nrf2 expression was alleviated by an inhibitor of nuclear factor-κB (NF-κB) (pyrrolidine dithiocarbamate) and small interfering RNA specific to NF-κB p65. DN+IS, DH, and DH+IS rats showed decreased renal expression of Nrf2 and its downstream target genes, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and increased renal expression of 8-hydroxydeoxyguanosine (8-OHdG), a marker of reactive oxygen species (ROS), compared with DN. Thus, indoxyl sulfate, as well as hypertension, downregulated renal expression of Nrf2 in rats. AST-120 upregulated renal expression of Nrf2, HO-1 and NQO1 and suppressed renal expression of 8-OHdG compared with control CKD rats. Indoxyl sulfate downregulates renal expression of Nrf2 through activation of NF-κB, followed by downregulation of HO-1 and NQO1 and increased production of ROS. Further, AST-120 upregulates renal expression of Nrf2 in CKD rats by removing serum indoxyl sulfate, followed by upregulation of HO-1 and NQO1 and decreased production of ROS.