title: Fn14 in podocytes and proteinuric kidney disease.
abstract: 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 NFκB 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 NFκB and increased MCP-1 mRNA and protein, an effect prevented by the NFκB inhibitor parthenolide. In conclusion, Fn14 activation results in NFκB-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immune origin.
authors.affiliation: Servicio de Nefrologia, IdiPAZ, Madrid 28046, Spain.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Jonay
authors.initials: J
authors.lastname: Poveda
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Sanz
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fernandez-Fernandez
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Hodgin
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D026501:Blotting, Southwestern; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000074049:Cytokine TWEAK; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
keywords: Fn14; Focal segmental glomerulosclerosis; Kidney; Podocyte; Proteinuria; TWEAK