Fn14 in podocytes and proteinuric kidney disease
Fn14 in podocytes and proteinuric kidney disease
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DOI：
10.1016/j.bbadis.2013.08.010
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发表时间：
2013-12-01
影响因子：
6.2
通讯作者：
Ortiz, Alberto
中科院分区：
文献类型：
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作者：
Dolores Sanchez-Nino, Maria;Poveda, Jonay;Ortiz, Alberto
非增殖性蛋白尿疾病是最常见的原发性肾小球疾病，可导致终末期肾病。这些疾病可能与低水平肾小球炎症和足细胞表达炎症介质有关。然而，在非免疫性疾病中，调节足细胞表达炎症介质的因素在体内知之甚少。我们现在已经探索了1 WEAK受体Fn 14在培养足细胞中介导肾小球炎症以及在实验性和人类非免疫性蛋白尿中的调节和作用。转录组学揭示了Fn 14和MCP-1 mRNA在局灶节段性肾小球硬化患者肾小球中的上调，以及两种转录本表达之间的相关性。在第二个局灶节段性肾小球硬化队列中证实了肾小球Fn 14和MCP-1 mRNA的增加，在膜性肾病中也观察到了这一点。在人类非增殖性蛋白尿肾病中，足细胞显示Fn 14和MCP-1表达以及NF κ B B活化。足细胞Fn 14在小鼠蛋白超载诱导的蛋白尿中增加。在Fn 14基因敲除小鼠与蛋白超载诱导的蛋白尿，肾小球和肾小球周围的巨噬细胞浸润减少，是MCP-1 mRNA和足细胞MCP-1染色和足细胞数量相比，野生型同行保存。腺病毒介导的TWEAK过表达增加了先前无肾损伤的小鼠的肾小球周围巨噬细胞浸润。在培养的足细胞中，炎性细胞因子增加Fn 14 mRNA和蛋白水平。TWEAK激活NF κ B并增加MCP-1 mRNA和蛋白质，NF κ B抑制剂parthenopropyl可阻止这种作用。总之，Fn 14激活导致NF κ B介导的足细胞促炎作用，这可能与非免疫起源的非增殖性蛋白尿肾病的发病机制有关。(C)2013爱思唯尔有限公司版权所有。
Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing end-stage renal disease. These disorders may associate low level glomerular inflammation and podocyte expression of inflammatory mediators. However, the factors regulating podocyte expression of inflammatory mediators in vivo in non-immune disorders are poorly understood. We have now explored the regulation and role of 1WEAK receptor Fn14 in mediating glomerular inflammation in cultured podocytes and in experimental and human non-immune proteinuria. Transcriptomics disclosed Fn14 and MCP-1 mRNA upregulation in glomeruli from patients with focal segmental glomerulosclerosis, as well as a correlation between the expression of both transcripts. Increased glomerular Fn14 and MCP-1 mRNA was confirmed in a second focal segmental glomerulosclerosis cohort and was also observed in membranous nephropathy. In human non-proliferative proteinuric kidney diseases podocytes displayed Fn14 and MCP-1 expression and NF kappa B activation. Podocyte Fn14 was increased in murine protein overload-induced proteinuria. In Fn14 knock-out mice with protein overload-induced proteinuria, glomerular and periglomerular macrophage infiltrates were reduced, as were MCP-1 mRNA and podocyte MCP-1 staining and podocyte numbers preserved as compared to wild-type counterparts. Adenovirus-mediated overexpression of TWEAK increased periglomerular macrophage infiltration in mice without prior kidney injury. In cultured podocytes inflammatory cytoldnes increased Fn14 mRNA and protein levels. TWEAK activated NF kappa B and increased MCP-1 mRNA and protein, an effect prevented by the NF kappa B inhibitor parthenolide. In conclusion, Fn14 activation results in NF kappa B-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immurie origin. (C) 2013 Elsevier B.V. All rights reserved.