PDF(Pubmed)
Abstract：
Farnesoid X receptor (FXR), a ligand-activated transcription factor, plays an important role in maintaining water homeostasis by up-regulating aquaporin 2 (AQP2) expression in renal medullary collecting ducts; however, its role in the survival of renal medullary interstitial cells (RMICs) under hypertonic conditions remains unclear. We cultured primary mouse RMICs and found that the FXR was expressed constitutively in RMICs, and that its expression was significantly up-regulated at both mRNA and protein levels by hypertonic stress. Using luciferase and ChIP assays, we found a potential binding site of nuclear factor kappa-B (NF-κB) located in the FXR gene promoter which can be bound and activated by NF-κB. Moreover, hypertonic stress-induced cell death in RMICs was significantly attenuated by FXR activation but worsened by FXR inhibition. Furthermore, FXR increased the expression and nuclear translocation of hypertonicity-induced tonicity-responsive enhance-binding protein (TonEBP), the expressions of its downstream target gene sodium myo-inositol transporter (SMIT), and heat shock protein 70 (HSP70). The present study demonstrates that the NF-κB/FXR/TonEBP pathway protects RMICs against hypertonic stress.
摘要：
法尼醇X受体（FXR），配体激活的转录因子，通过上调水通道蛋白2(AQP2)在肾髓样集合管中的表达对维持水稳态具有重要作用;其在高渗条件下肾髓质间质细胞(RMICs)存活中的作用尚不清楚.我们培养了原代小鼠RMIC，发现FXR在RMIC中组成型表达，高渗应激在mRNA和蛋白质水平均显著上调其表达。使用荧光素酶和ChIP测定，我们在FXR基因启动子中发现了核因子κB（NF-κB）的潜在结合位点，该位点可以被NF-κB结合并激活。此外，FXR激活可显着减弱高渗应激诱导的RMIC细胞死亡，但FXR抑制可显着减弱。此外，FXR增加了高张力诱导的张力响应增强结合蛋白（TonEBP）的表达和核易位，其下游靶基因肌醇钠转运蛋白（SMIT）的表达，和热休克蛋白70（HSP70）。本研究表明NF-κB/FXR/TonEBP途径保护RMIC免受高渗应激。
