Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis
Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis
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DOI：
10.1152/ajprenal.00414.2019
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发表时间：
2020-03-01
影响因子：
4.2
通讯作者：
Nagata, Michio
中科院分区：
文献类型：
--
作者：
Ito, Naoko;Sakamoto, Kazuo;Nagata, Michio
肾小球壁上皮细胞（PEC）活化，如CD 44从头表达和细胞向受损滤过屏障迁移所示，是足细胞损伤驱动的局灶节段性肾小球硬化（FSGS）的标志。然而，介导佩奇激活的信号通路对足细胞损伤的反应是未知的。本研究的重点是CD 44信号，特别是两个CD 44相关的趋化因子，迁移抑制因子（MIF）和基质细胞衍生因子1（SDF 1），以及它们的共同受体，趋化因子（C-X-C基序）受体4（CXCR 4），在FSGS的NEP 25/LMB 2小鼠足细胞毒素模型中的作用。在疾病的早期阶段，CD 44阳性佩奇在完整肾小球簇的对侧局部明显，随后在粘连附近增加，伴有足细胞丢失。MIF和SUFI的表达首先在受损足细胞中增加，随后转移到表达CD 44和CXCR 4的活化佩奇。在永生化小鼠PEC（mPEC）系中，重组MIF和SDF 1（分别为rMIF和rSDF 1）分别增加CD 44和CXCR 4 mRNA和蛋白水平。rMIF和rSDF 1刺激内源性MIF和SDF 1的产生。rMIF和rSDF 1诱导的mPEC迁移被CD 44 siRNA抑制。然而，MIF和SDF 1抑制剂对NEP 25/LMB 2小鼠的蛋白尿、足细胞数量和CD 44表达没有任何影响。我们的数据表明，受伤的足细胞上调MIF和SDF 1，刺激CD 44的表达和CD 44介导的迁移，这是增强内源性MIF和SDF 1在佩奇。足细胞和佩奇中趋化因子-CD 44轴的这种双相表达模式可能是足细胞损伤驱动FSGS的“足细胞-PEC串扰”信号传导的新机制。
Glomerular parietal epithelial cell (PEC) activation, as revealed by de novo expression of CD44 and cell migration toward the injured filtration barrier, is a hallmark of podocyte injurydriven focal segmental glomerulosclerosis (FSGS). However, the signaling pathway that mediates activation of PECs in response to podocyte injury is unknown. The present study focused on CD44 signaling, particularly the roles of two CD44-related chemokines, migration inhibitory factor (MIF) and stromal cell-derived factor 1 (SDF1), and their common receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), in the NEP25/LMB2 mouse podocyte-toxin model of FSGS. In the early phase of the disease, CD44-positive PECs were locally evident on the opposite side of the intact glomerular tuft and subsequently increased in the vicinity of synechiae with podocyte loss. Expression of MIF and SUFI was first increased in injured podocytes and subsequently transferred to activated PECs expressing CD44 and CXCR4. In an immortalized mouse PEC (mPEC) line, recombinant MIF and SDF1 (rMIF and rSDF1, respectively) individually increased CD44 and CXCR4 mRNA and protein levels. rMIF and rSDF1 stimulated endogenous MIF and SDF1 production. rMIF- and rSDF1-induced mPEC migration was suppressed by CD44 siRNA. However, MIF and SDF1 inhibitors failed to show any impact on proteinuria, podocyte number, and CD44 expression in NEP25/ LMB2 mice. Our data suggest that injured podocytes upregulate MIF and SDF1 that stimulate CD44 expression and CD44-mediated migration, which is enhanced by endogenous MIF and SDF1 in PECs. This biphasic expression pattern of the chemokine-CD44 axis in podocytes and PECs may be a novel mechanism of "podocyte-PEC cross-talk" signaling underlying podocyte injury-driven FSGS.