title: Antiviral innate immunity disturbs podocyte cell function.
abstract: Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis throughout the world. A majority (approx. 60%) of patients with IgAN experience disease exacerbations associated with an acute respiratory or gastrointestinal illness that appears to represent a viral infection. However, the exact mechanism of the disease exacerbation by viral infection is not understood, especially at the cellular and molecular levels. Here we report that glomerular podocytes express the major sensors for double-stranded RNA (dsRNA), a common byproduct of viral replication. In addition to these receptors, Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I)-like helicases (RLHs), podocytes express the collateral proteins required to support intracellular signaling. The pathways that mediate responses to dsRNA are fully functional in podocytes. The transcription factor interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-ĸB) are phosphorylated and translocate to the nucleus, and dsRNA increases synthesis of proteins driven by IRF3 (P54, P56 and P60) or NF-ĸB (interleukin 8 and A20). Furthermore, dsRNA suppresses podocyte cell migration, alters the expression of a panel of podocyte essential proteins (nephrin, podocin and CD2-associated protein or CD2AP) and changes transepithelial albumin flux. These effects are dsRNA sensor-specific: TLR3-/- podocytes do not respond to extracellular dsRNA, while intracellular dsRNA has no effect on podocytes bearing a dominant negative form of the major active RLH. These results demonstrate that innate responses to viruses can disturb podocyte cell function in vitro.
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Cleveland Clinic, Cleveland, OH 44106, USA. mxy53@cwru.edu
authors.forename: Michifumi
authors.initials: M
authors.lastname: Yamashita
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Millward
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoshita
authors.forename: Paramananda
authors.initials: P
authors.lastname: Saikia
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Steven N
authors.initials: SN
authors.lastname: Emancipator
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D050199:Podocytes / Q000276:immunology* / Q000473:pathology; D012330:RNA, Double-Stranded / Q000276:immunology* / Q000494:pharmacology; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D014777:Virus Diseases / Q000150:complications / Q000276:immunology / Q000473:pathology; D000097905:Roundabout Proteins
chemical_list: D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D012330:RNA, Double-Stranded; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; C494233:Irf3 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C519703:TLR3 protein, mouse