Salt suppresses IFNγ inducible chemokines through the IFNγ-JAK1-STAT1 signaling pathway in proximal tubular cells

Sci Rep. 2017 Apr 20;7:46580. doi: 10.1038/srep46580.

Abstract

The mechanisms of immunoactivation by salt are now becoming clearer. However, those of immunosuppression remain unknown. Since clinical evidence indicates that salt protects proximal tubules from injury, we investigated mechanisms responsible for salt causing immunosuppression in proximal tubules. We focused on cytokine-related gene expression profiles in kidneys of mice fed a high salt diet using microarray analysis and found that both an interferon gamma (IFNγ) inducible chemokine, chemokine (C-X-C motif) ligand 9 (CXCL9), and receptor, CXCR3, were suppressed. We further revealed that a high salt concentration suppressed IFNγ inducible chemokines in HK2 proximal tubular cells. Finally, we demonstrated that a high salt concentration decreased IFNGR1 expression in the basolateral membrane of HK2 cells, leading to decreased phosphorylation of activation sites of Janus kinase 1 (JAK1) and Signal Transducers and Activator of Transcription 1 (STAT1), activators of chemokines. JAK inhibitor canceled the effect of a high salt concentration on STAT1 and chemokines, indicating that the JAK1-STAT1 signaling pathway is essential for this mechanism. In conclusion, a high salt concentration suppresses IFNγ-JAK1-STAT1 signaling pathways and chemokine expressions in proximal tubules. This finding may explain how salt ameliorates proximal tubular injury and offer a new insight into the linkage between salt and immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Cell Line
  • Chemokines / genetics*
  • Chemokines / metabolism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology*
  • Janus Kinase 1 / metabolism
  • Kidney Tubules, Proximal / cytology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Sodium Chloride / pharmacology*
  • Transcriptome / drug effects
  • Transcriptome / genetics

Substances

  • Antiviral Agents
  • Chemokines
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • interferon gamma receptor
  • Sodium Chloride
  • Interferon-gamma
  • Janus Kinase 1