Wuhu Hospital, East China Normal University, Wuhu, Anhui, China.
Health Science Center, East China Normal University, Shanghai, China.
J Cell Mol Med. 2024 May;28(10):e18409. doi: 10.1111/jcmm.18409.
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.
法尼醇 X 受体 (FXR) 是一种配体激活的转录因子，通过上调肾脏髓质集合管中水通道蛋白 2 (AQP2) 的表达，在维持水稳态中发挥重要作用；然而，其在高渗条件下对肾脏髓质间充质细胞 (RMICs) 存活的作用尚不清楚。我们培养了原代小鼠 RMICs，并发现 FXR 在 RMICs 中持续表达，其表达在 mRNA 和蛋白质水平上均被高渗应激显著上调。通过荧光素酶和 ChIP 测定，我们发现了核因子 kappa-B (NF-κB) 在 FXR 基因启动子中的一个潜在结合位点，该位点可被 NF-κB 结合并激活。此外，FXR 激活显著减轻了 RMICs 中高渗诱导的细胞死亡，而 FXR 抑制则加重了这种细胞死亡。此外，FXR 增加了高渗诱导的张力应答增强结合蛋白 (TonEBP) 的表达和核易位，及其下游靶基因钠肌醇转运蛋白 (SMIT) 和热休克蛋白 70 (HSP70) 的表达。本研究表明，NF-κB/FXR/TonEBP 通路可保护 RMICs 免受高渗应激。
