title: Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria.
abstract: The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1–6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro-inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7-1 expression and actin remodelling in vitro and transient proteinuria in vivo. Importantly, the treatment of mice with a type I IFN receptor-blocking antibody (Ab) prevents LPS-induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection- or inflammation-induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti-IFN Abs may be a novel therapy for proteinuric kidney diseases.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Gurkan
authors.forename: Allison
authors.initials: A
authors.lastname: Cabinian
authors.forename: Victoria
authors.initials: V
authors.lastname: Lopez
authors.forename: Mantu
authors.initials: M
authors.lastname: Bhaumik
authors.forename: Jer-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Rabson
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D007370:Interferon Type I / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D008024:Ligands; D051193:Toll-Like Receptors