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Original ArticlesGlomerular and Tubulointerstitial Diseases
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JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy

Jianling Tao, Laura Mariani, Sean Eddy, Holden Maecker, Neeraja Kambham, Kshama Mehta, John Hartman, Weiqi Wang, Matthias Kretzler and Richard A. Lafayette
CJASN July 2020, 15 (7) 973-982; DOI: https://doi.org/10.2215/CJN.11010919
Jianling Tao
1Department of Medicine, Stanford University Medical Center, Stanford, California
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Laura Mariani
2Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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Sean Eddy
2Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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Holden Maecker
1Department of Medicine, Stanford University Medical Center, Stanford, California
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Neeraja Kambham
1Department of Medicine, Stanford University Medical Center, Stanford, California
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Kshama Mehta
1Department of Medicine, Stanford University Medical Center, Stanford, California
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John Hartman
2Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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Weiqi Wang
1Department of Medicine, Stanford University Medical Center, Stanford, California
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Matthias Kretzler
2Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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Richard A. Lafayette
1Department of Medicine, Stanford University Medical Center, Stanford, California
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Abstract

Background and objectives IgA nephropathy is the most common primary glomerular disease in the world. Marked by mesangial inflammation and proliferation, it generally leads to progressive kidney fibrosis. As the Janus kinase signal transducer and activator of transcription pathway has been implicated as an important mediator of diabetic kidney disease and FSGS, detailed investigation of this pathway in IgA nephropathy was undertaken to establish the basis for targeting this pathway across glomerular diseases.

Design, setting, participants, & measurements Well characterized patients with IgA nephropathy and controls were studied, allowing us to compare 77 patients with biopsy-proven IgA nephropathy with 45 healthy subjects. STAT phosphorylation was assessed in peripheral blood monocytes (PBMCs) by phosphoflow before and after cytokine stimulation. Kidney Janus kinase signal transducer and activator of transcription activity was studied by immunofluorescence and by transcriptomic studies. An STAT1 activity score was established using downstream transcriptional targets of pSTAT1 and associated with disease and clinical outcomes.

Results We found PBMCs to have upregulated pSTAT production at baseline in patients with IgA nephropathy with a limited reserve to respond to cytokine stimulation compared with controls. Increased staining in glomerular mesangium and endothelium was seen for Jak-2 and pSTAT1 and in the tubulointerstitial for JAK2, pSTAT1, and pSTAT3. Activation of the Janus kinase signal transducer and activator of transcription pathway was further supported by increased pSTAT1 and pSTAT3 scores in glomerular and tubulointerstitial sections of the kidney (glomerular activation Z scores: 7.1 and 4.5, respectively; P values: <0.001 and <0.001, respectively). Clinically, phosphoflow results associated with proteinuria and kidney function, and STAT1 activation associated with proteinuria but was not associated with progression.

Conclusions Janus kinase signal transducer and activator of transcription signaling was activated in patients with IgA nephropathy compared with controls. There were altered responses in peripheral immune cells and increased message and activated proteins in the kidney. These changes variably related to proteinuria and kidney function.

  • IgA nephropathy
  • Cell Signaling
  • gene transcription
  • pathology
  • Glomerulonephritis
  • IGA
  • Glomerular Mesangium
  • Diabetic
  • Nephropathies
  • Glomerulosclerosis
  • Focal Segmental
  • Phosphorylation
  • Monocytes
  • Leukocytes
  • Mononuclear
  • Transcriptome
  • Kidney
  • Glomerulus
  • JAK2 protein
  • human
  • Janus Kinase 2
  • kidney
  • proteinuria
  • Biopsy
  • Received September 12, 2019.
  • Accepted April 2, 2020.
  • Copyright © 2020 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 15 (7)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 7
July 01, 2020
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JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy
Jianling Tao, Laura Mariani, Sean Eddy, Holden Maecker, Neeraja Kambham, Kshama Mehta, John Hartman, Weiqi Wang, Matthias Kretzler, Richard A. Lafayette
CJASN Jul 2020, 15 (7) 973-982; DOI: 10.2215/CJN.11010919

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JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy
Jianling Tao, Laura Mariani, Sean Eddy, Holden Maecker, Neeraja Kambham, Kshama Mehta, John Hartman, Weiqi Wang, Matthias Kretzler, Richard A. Lafayette
CJASN Jul 2020, 15 (7) 973-982; DOI: 10.2215/CJN.11010919
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Keywords

  • IgA nephropathy
  • Cell Signaling
  • gene transcription
  • pathology
  • Glomerulonephritis
  • IGA
  • Glomerular Mesangium
  • Diabetic
  • Nephropathies
  • Glomerulosclerosis
  • Focal Segmental
  • Phosphorylation
  • Monocytes
  • Leukocytes
  • Mononuclear
  • Transcriptome
  • kidney
  • glomerulus
  • JAK2 protein
  • human
  • Janus Kinase 2
  • proteinuria
  • Biopsy

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