Fn14 in podocytes and proteinuric kidney disease

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• 作者：Maria Dolores Sanchez-Ni帽o ; Jonay Poveda ; Ana Belen Sanz ; Sergio Mezzano ; Susana Carrasco ; Beatriz Fern ; ez-Fern ; ez ; Linda C. Burkly ; Viji Nair ; Matthias Kretzler ; Jeffrey B. Hodgin ; Marta Ruiz-Ortega ; Rafael Selgas ; Jesus Egido ; Alberto Ortiz
• 关键词：Fn14 ; Focal segmental glomerulosclerosis ; Kidney ; Podocyte ; Proteinuria ; TWEAK
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：December, 2013
• 年：2013
• 卷：1832
• 期：12
• 页码：2232-2243
• 全文大小：2401 K

文摘

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 TWEAK 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魏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 cytokines increased Fn14 mRNA and protein levels. TWEAK activated NF魏B and increased MCP-1 mRNA and protein, an effect prevented by the NF魏B inhibitor parthenolide. In conclusion, Fn14 activation results in NF魏B-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immune origin.