Activation of liver X receptor suppresses osteopontin expression and ameliorates nephrolithiasis
Activation of liver X receptor suppresses osteopontin expression and ameliorates nephrolithiasis
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肝脏X受体的激活抑制骨桥蛋白表达并改善肾结石
DOI：
10.1002/jcp.28101
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Tang, Xiao-Jing
中科院分区：
文献类型：
--
作者：
Chen, Jie;Zhang, Di;Tang, Xiao-Jing
肾结石是一种常见的泌尿系统疾病，特别是特发性草酸钙(CaOx)结石是其特殊类型之一。在CaOx肾结石形成的最初阶段，兰德尔斑块(RPS)形成。肝X受体(LXRs)在其他疾病中抑制氧化应激和炎症反应；然而，LXRs在肾结石中的作用尚不清楚。本研究探讨了LXRs在RP形成过程中的作用。基因芯片分析显示，LXR/RXR水平在低斑块组织中显著升高(5%)，证实了LXR激活和RP形成之间的联系。相应地，两个LXR靶基因LXR和LXR在高斑块组织中的表达水平低于低斑块组织。在体外，LXR激动剂可减轻一水草酸钙诱导的细胞钙沉积和细胞凋亡。LXR的激活减少了活性氧的产生和炎症介质的基因表达，包括最近被证明与RPS的发展相关的骨桥蛋白。此外，p38MAPK和JNK信号通路可能介导了LXR在HK-2细胞中的表达。在动物模型中，通过激活LXR来减少沉积，骨桥蛋白的表达也受到抑制。我们的发现提示LXRs在特发性CaOx肾结石的进展中起作用；LXR激动剂可能具有治疗肾结石的潜力。
Nephrolithiasis is a common disease of the urinary system, of which idiopathic calcium oxalate (CaOx) kidney stones, in particular, are one of the special types. In the initial stages of CaOx kidney stone formation, Randall's plaques (RPs) develop. Liver X receptors (LXRs) inhibit oxidative stress and inFLammatory in other diseases; nevertheless, the role of LXRs in nephrolithiasis has yet to be elucidated. In this study, the role of LXRs in the progression of RP formation was investigated. Microarray analysis revealed that LXR/RXR levels were significantly greater in low-plaque tissues (5%), confirming the link between LXR activation and RP formation. Correspondingly, expression levels of two LXR target genes, LXR and LXR, were lower in high-plaque tissues than in low-plaque tissues. In vitro, LXR agonist alleviated calcium oxalate monohydrate-induced cellular calcium deposits and apoptosis. LXR activation decreased reactive oxygen species production and gene expression of inflammatory mediators, including osteopontin that has recently been demonstrated to correlate with the development of RPs. Moreover, p38 MAPK and JNK signaling may mediate LXR-regulated expression in HK-2 cells. In an animal model, the deposition was reduced by activating LXR, and osteopontin expression was also inhibited. Our findings suggest a role for LXRs in the progression of idiopathic CaOx kidney stones; LXR agonists may have therapeutic potential for the treatment of nephrolithiasis.