期刊
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 15, 期 7, 页码 973-982出版社
AMER SOC NEPHROLOGY
DOI: 10.2215/CJN.11010919
关键词
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
资金
- Nephrotic Syndrome Study Network Consortium (NEPTUNE), part of National Institutes of Health rare disease clinical research network grant [U54 DK083912]
- Office of Rare Diseases Research, National Center for Advancing Translational Sciences
- National Institute of Diabetes, Digestive, and Kidney Diseases
- Applied Systems Biology Core at the University ofMichigan IgA nephropathy George M. O'Brien Kidney Translational Core Center [P30 DK081943]
- NephCure Kidney International
- Halpin Foundation
- John and Abby Sobrato Fund
- Else Kroner-Fresenius-Stiftung (European Renal cDNA Bank)
- George and Angeliki Perlegos Fund
Background and objectivesIgA 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.ResultsWe 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.ConclusionsJanus 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.
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