Sheng Xuxiang, Zuo Xiaoyan, Liu Xihui, Zhou Yang, Sun Xia
Department of Nephrology, Linyi People's Hospital, Linyi, 276003, Shandong, People's Republic of China.
Department of Nephrology, Yiyuan People's Hospital, Zibo, Shandong, People's Republic of China.
Int Urol Nephrol. 2018 Apr;50(4):779-785. doi: 10.1007/s11255-017-1760-2. Epub 2017 Dec 11.
IgA nephropathy (IgAN) is an immune complex-mediated disease involved in the kidney disease. Recent studies have revealed that Notch signaling-related genes are aberrantly expressed in various cell types and maybe associate with inflammation-induced carcinogenesis. The aim of our study was to investigate the function of Notch1 in the inflammatory response of IgAN.
The expression of Notch1, Jagged1 and NICD1 in 52 IgAN renal tissues and 20 control renal tissues was first determined using quantitative real-time PCR and Western blot. ELISA was then used to estimate the inflammatory response of human podocytes to LPS. NF-κB activity was measured using dual-luciferase reporter assay. Activation of Notch1 and NF-κB signaling pathway was assessed using Western blot.
The expression of Notch1, NICD1 and Jagged1 was significantly higher in IgAN renal tissues than control renal tissues (P < 0.05). LPS treatment resulted in an obvious increase of MCP-1, IL-8 and phosphorylated NF-κB p65 in podocytes polymeric IgA (pIgA) IgAN group compared to control group (P < 0.05 for all). Activated Notch1 and its target genes, Hes1 and Hey1 were also enhanced upon LPS stimulation. Silencing of Notch1 signaling with inhibitor DAPT, NF-κB activation and LPS-induced inflammatory response were obviously attenuated, whereas Notch1 activator Jagged1 could markedly restore NF-κB activity and LPS-induced inflammatory response (P < 0.05 for all).
Crosstalk between TLR4 and Notch1 signaling regulates the inflammatory response in the IgAN and maybe plays an important role in the progression of IgAN.
IgA肾病（IgAN）是一种免疫复合物介导的肾脏疾病。最近的研究表明，Notch信号相关基因在多种细胞类型中异常表达，可能与炎症诱导的致癌作用有关。我们研究的目的是探讨Notch1在IgAN炎症反应中的作用。
首先采用定量实时PCR和蛋白质免疫印迹法检测52例IgAN肾组织和20例对照肾组织中Notch1、Jagged1和NICD1的表达。然后用酶联免疫吸附测定法评估人足细胞对脂多糖（LPS）的炎症反应。采用双荧光素酶报告基因检测法测定核因子κB（NF-κB）活性。通过蛋白质免疫印迹法评估Notch1和NF-κB信号通路的激活情况。
IgAN肾组织中Notch1、NICD1和Jagged1的表达明显高于对照肾组织（P<0.05）。与对照组相比，LPS处理导致多聚IgA（pIgA）IgAN组足细胞中单核细胞趋化蛋白-1（MCP-1）、白细胞介素-8（IL-8）和磷酸化NF-κB p65明显增加（均P<0.05）。LPS刺激后，活化的Notch1及其靶基因Hes1和Hey1也增强。用抑制剂DAPT沉默Notch1信号后，NF-κB激活和LPS诱导的炎症反应明显减弱，而Notch1激活剂Jagged1可显著恢复NF-κB活性和LPS诱导的炎症反应（均P<0.05）。
Toll样受体4（TLR4）和Notch1信号之间的相互作用调节IgAN中的炎症反应，可能在IgAN的进展中起重要作用。
