Yiu Wai Han, Chan Kam Wa, Chan Loretta Y Y, Leung Joseph C K, Lai Kar Neng, Tang Sydney C W
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Front Physiol. 2021 Mar 15;12:650888. doi: 10.3389/fphys.2021.650888. eCollection 2021.
Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in signal transduction in a variety of immune responses. It has been demonstrated that Syk plays a pathogenic role in orchestrating inflammatory responses and cell proliferation in human mesangial cells (HMC) in IgA nephropathy (IgAN). However, whether Syk is involved in tubular damage in IgAN remains unknown. Using human kidney biopsy specimens, we found that Syk was activated in renal tubules of biopsy-proven IgAN patients with an increase in total and phosphorylated levels compared to that from healthy control subjects. , cultured proximal tubular epithelial cells (PTECs) were stimulated with conditioned medium prepared from human mesangial cells incubated with polymeric IgA (IgA-HMC) from patients with IgAN or healthy control. Induction of IL-6, IL-8, and ICAM-1 synthesis from cultured PTECs incubated with IgA-HMC conditioned medium was significantly suppressed by treatment with the Syk inhibitor R406 compared to that from healthy control. Furthermore, R406 downregulated expression of phosphorylated p65 NF-κB and p-42/p-44 MAPK, and attenuated TNF-α-induced cytokine production in PTECs. Taken together, our findings suggest that Syk mediates IgA-HMC conditioned medium-induced inflammation in tubular cells activation of NF-κB and p-42/p-44 MAPK signaling. Inhibition of Syk may be a potential therapeutic approach for tubulointerstitial injury in IgAN.
脾酪氨酸激酶（Syk）是一种非受体酪氨酸激酶，参与多种免疫反应中的信号转导。已证明Syk在IgA肾病（IgAN）的人肾小球系膜细胞（HMC）中协调炎症反应和细胞增殖方面发挥致病作用。然而，Syk是否参与IgAN中的肾小管损伤仍不清楚。使用人肾活检标本，我们发现与健康对照受试者相比，经活检证实的IgAN患者肾小管中的Syk被激活，总水平和磷酸化水平均增加。用来自IgAN患者或健康对照的聚合IgA（IgA-HMC）孵育的人肾小球系膜细胞制备的条件培养基刺激培养的近端肾小管上皮细胞（PTEC）。与健康对照相比，用Syk抑制剂R406处理可显著抑制用IgA-HMC条件培养基孵育的培养PTEC中IL-6、IL-8和ICAM-1合成的诱导。此外，R406下调磷酸化p65 NF-κB和p-42/p-44 MAPK的表达，并减弱TNF-α诱导的PTEC中细胞因子的产生。综上所述，我们的研究结果表明，Syk介导IgA-HMC条件培养基诱导的肾小管细胞炎症——NF-κB和p-42/p-44 MAPK信号通路的激活。抑制Syk可能是IgAN肾小管间质损伤的一种潜在治疗方法。
