Podocytes contribute, and respond, to the inflammatory environment in lupus nephritis.
Podocytes contribute, and respond, to the inflammatory environment in lupus nephritis.
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DOI：
10.1152/ajprenal.00512.2017
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发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Beresford MW
中科院分区：
文献类型：
--
作者：
Wright RD;Beresford MW
狼疮性肾炎（LN）影响高达80%的青少年发作的系统性红斑狼疮患者，导致终末期肾衰竭，需要透析或移植的10- 15%。足细胞是肾小球的特化上皮细胞，已知是肾小球疾病中损伤的关键部位。然而，他们在LN中的角色尚未完全确定。本研究旨在探讨足细胞在LN体外模型中的结构和功能作用。在体外LN模型中，用促炎细胞因子（IL-1β、TNF-α、IFN-α和IFN-γ）单独和联合处理永生化足细胞，并评估其结构和功能特征。在基础条件下，足细胞产生相对较低水平的TNF-α、IL-6、IL-8、VEGF、粒细胞-单核细胞集落刺激因子（GM-CSF）和巨噬细胞集落刺激因子（M-CSF）; IL-1β刺激导致IL-6（P = 0.011）、IL-8（P = 0.05）、VEGF（P = 0.02）和M-CSF（P = 0.03）分泌增加。用TNF-α刺激导致M-CSF分泌增加（P = 0.049），用IFN-γ刺激导致IL-10（P = 0.036）和IFN-γ诱导蛋白-10（P = 0.036）的新产生。足细胞显示，IL-1β处理后1小时内，丝状肌动蛋白覆盖的面积减少（P = 0.011），24小时后恢复，这与细胞内钙水平的增加有关，但与细胞死亡的增加无关。足细胞通过细胞因子/趋化因子分泌促进LN中的炎性环境，并通过肌动蛋白细胞骨架的重排对炎性环境做出反应，从而导致消失，这是一种众所周知的保护这些细胞免于凋亡的方法。这表明足细胞参与LN的发病机制。
Lupus nephritis (LN) affects up to 80% of juvenile onset systemic lupus erythematosus patients, leading to end stage renal failure requiring dialysis or transplantation in 10–15%. Podocytes are specialized epithelial cells of the glomerulus known to be a key site of damage in glomerular diseases. However, their roles in LN have yet to be fully identified. This project aims to identify structural and functional roles of podocytes in an in vitro model of LN. Conditionally immortalized podocytes were treated with proinflammatory cytokines (IL-1β, TNF-α, IFN-α, and IFN-γ) alone and in combination in an in vitro model of LN and were assessed for their structural and functional characteristics. Podocytes produce TNF-α, IL-6, IL-8, VEGF, granulocyte-monocyte colony stimulating factor (GM-CSF), and macrophage colony stimulating factor (M-CSF) at relatively low levels under basal conditions; stimulation with IL-1β led to increased secretion of IL-6 (P = 0.011), IL-8 (P = 0.05), VEGF (P = 0.02), and M-CSF (P = 0.03). Stimulation with TNF-α led to increased secretion of M-CSF (P = 0.049) and stimulation with IFN-γ led to novel production of IL-10 (P = 0.036) and interferon-γ-inducible protein-10 (P = 0.036). Podocytes demonstrate a reduction in the area covered by filamentous-actin in response to IL-1β treatment within 1 h (P = 0.011), which is restored by 24 h, associated with an increase in the level of intracellular calcium but not with increased cell death. Podocytes contribute to the inflammatory milieu in LN through cytokine/chemokine secretion and respond to the inflammatory milieu via rearrangement of the actin cytoskeleton leading to effacement, a well-known method of protection against apoptosis in these cells. This demonstrates that podocytes are involved in the pathogenesis of LN.
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