JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis

Kidney Int. 2018 Oct;94(4):795-808. doi: 10.1016/j.kint.2018.05.022. Epub 2018 Aug 6.

Abstract

Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT 1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.

Keywords: cell signaling; focal segmental glomerulosclerosis; gene expression; lymphocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Case-Control Studies
  • Female
  • Gene Expression Profiling
  • Glomerulosclerosis, Focal Segmental / blood
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / immunology
  • Glomerulosclerosis, Focal Segmental / metabolism*
  • Humans
  • Janus Kinase 1 / blood
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism*
  • Janus Kinase 2 / blood
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Kidney Glomerulus / metabolism
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Phosphorylation
  • STAT1 Transcription Factor / blood
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • STAT3 Transcription Factor / blood
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcriptome
  • Young Adult

Substances

  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2