Antiviral innate immunity disturbs podocyte cell function

Michifumi Yamashita, Carrie A. Millward, Hiroyuki Inoshita, Paramananda Saikia, Saurabh Chattopadhyay, Ganes C. Sen, Steven N. Emancipator

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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-κB) are phosphorylated and translocate to the nucleus, and dsRNA increases synthesis of proteins driven by IRF3 (P54, P56 and P60) or NF-κB (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.

Original languageEnglish
Pages (from-to)231-241
Number of pages11
JournalJournal of Innate Immunity
Volume5
Issue number3
DOIs
StatePublished - Apr 2013

Keywords

  • Glomerulopathy
  • Immunoglobulin A nephropathy
  • Podocyte cell function
  • Viral infection

ASJC Scopus subject areas

  • Immunology and Allergy

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