TNFα pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and β3 integrin activation.
Background: In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation....
| Publicado en: | Pediatric Nephrology Vol. 27; no. 12; pp. 2217 - 2227 |
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| Autores principales: | , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Springer Nature
Dec2012
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=83184825&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 83184825 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 0931041X EF1 jtl: Pediatric Nephrology issn: 0931041X maglogo: N pubinfo: dt: Dec2012 vid: 27 iid: 12 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 83184825 104434499 104434499 10.1007/s00467-012-2163-3 83184825 ppf: 2217 ppct: 10 formats: fmt: @attributes: type: P tig: atl: TNFα pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and β3 integrin activation. aug: au: Bitzan, Martin Babayeva, Sima Vasudevan, Anil Goodyer, Paul Torban, Elena affil: Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal Canada sug: subj: Tumor Necrosis Factor Antigens, Surface Glomerulonephritis Pathology Epithelial Cells Signal Transduction Human Cell Culture Techniques Child Female Fluorescent Antibody Technique T-Tests Analysis of Variance Descriptive Statistics In Vitro Studies Funding Source Data Analysis Software Child: 6-12 years Female ab: Background: In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS). Methods: Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFα) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy. Results: Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated β3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre-incubation with antibodies against TNFα or either of the two TNFα receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFα therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely. Conclusions: We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and β3 integrin-mediated podocyte attachment are driven by the TNFα pathway. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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