Keap1 inhibition attenuates glomerulosclerosis
Keap1 inhibition attenuates glomerulosclerosis
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DOI：
10.1093/ndt/gfu002
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发表时间：
2014-04-01
影响因子：
6.1
通讯作者：
Matsusaka, Taiji
中科院分区：
文献类型：
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作者：
Miyazaki, Yoichi;Shimizu, Akihiro;Matsusaka, Taiji
NFE2 相关因子 2 (Nrf2) 是抗氧化基因的主要调控转录因子。抑制其衔接蛋白 Kelch 样 ECH 相关蛋白 1 (Keap1)，可激活 Nrf2。足细胞损伤引发肾小球损伤逐渐恶化，导致肾小球硬化。我们检查了 Keap1-Nrf2 系统的调制是否对此过程有影响。方法。 Nrf2 无效突变 (KO) 和 Keap1 亚形性敲除 (KD) 小鼠与 NEP25 小鼠杂交，其中免疫毒素可诱导足细胞特异性损伤。结果。受损的NEP25肾脏中硫代巴比妥酸反应物质、8-羟基脱氧鸟苷和磷酸化JNK增加。实时PCR显示Keap1 KD上调Nrf2靶基因，包括肾小球中的Gclc、Gclm、Gstp1、Gstp2和Nqo1。然而，足细胞损伤并没有上调 Keap1 野生型小鼠中的这些基因，也没有进一步增加 Keap1 KD 小鼠中这些基因的表达。诱导足细胞损伤三周后，Keap1 KD 小鼠的肾小球硬化程度比对照小鼠明显减轻（中位硬化指数，0.27 与 3.03，0-4 级）。 Keap1 KD 小鼠还表现出显着保留的去氧肾上腺素染色（中位指数为 6.76 对比 0.91，0-8 级），含有结蛋白阳性损伤足细胞的肾小球减少（中位百分比为 24.5% 对比 85.8%），同时 Fn1、Tgfb1、Col4a4 和 Col1a2 的 mRNA 减少。结论。因此，足细胞损伤不能有效激活 Nrf2，但通过 Keap1 敲低激活 Nrf2 可减轻肾小球硬化。这些结果表明Nrf2-Keap1系统是治疗慢性肾脏疾病的有前途的药物靶点。
NFE2-related factor 2 (Nrf2) is a master regulatory transcription factor for antioxidant genes. Inhibition of its adaptor protein, Kelch-like ECH-associated protein 1 (Keap1), activates Nrf2. Podocyte injury triggers the progressive deterioration of glomerular damage toward glomerulosclerosis. We examined whether modulation of the Keap1-Nrf2 system has an impact on this process.Methods. Nrf2 null-mutant (KO) and Keap1 hypomorphic knockdown (KD) mice were crossed with NEP25 mice, in which podocyte-specific injury can be induced by an immunotoxin.Results. Thiobarbituric acid reactive substances, 8-hydroxy-deoxyguanosine and phosphorylated JNK were increased in the injured NEP25 kidney. Real-time PCR revealed that Keap1 KD upregulated Nrf2 target genes, including Gclc, Gclm, Gstp1, Gstp2 and Nqo1 in the glomerulus. However, podocyte injury did not upregulate these genes in Keap1 wild-type mice, nor did it further increase the expression of those genes in Keap1 KD mice. Three weeks after the induction of podocyte injury, glomerulosclerosis was considerably more attenuated in Keap1 KD mice than in control mice (median sclerosis index, 0.27 versus 3.03, on a 0-4 scale). Keap1 KD mice also showed considerably preserved nephrin staining (median index, 6.76 versus 0.91, on a 0-8 scale) and decreased glomeruli containing desmin-positive injured podocytes (median percentage, 24.5% versus 85.8%), along with a decrease in mRNAs for Fn1, Tgfb1, Col4a4 and Col1a2.Conclusions. Thus, podocyte injury cannot effectively activate Nrf2, but Nrf2 activation by Keap1 knockdown attenuates glomerulosclerosis. These results indicate that the Nrf2-Keap1 system is a promising drug target for the treatment of chronic kidney diseases.