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Abstract: TH-PO445

SH3BP2-Mediated Immune Activation in Idiopathic Nephrotic Syndrome (NS)

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Srivastava, Tarak, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States
  • Joshi, Trupti, University of Missouri, Columbia, Missouri, United States
  • Hao, Wei, University of Michigan, Ann Arbor, Michigan, United States
  • Wang, Yujie, University of Michigan, Ann Arbor, Michigan, United States
  • Gipson, Debbie, University of Michigan, Ann Arbor, Michigan, United States
  • Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
  • Sharma, Mukut, Kansas City VA Medical Center, Kansas City, Missouri, United States
Background

Immunopathogenesis of NS in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains largely unknown. SH3BP2, an adaptor protein, forms a signaling complex (signalosome) with Src, Syk, etc. to integrate immune signaling pathways involved in activation of T-, B-cells, MΦ, etc. Significance of the SH3BP2 signaling in NS-associated immune activation is not known.

Methods

RNA sequencing data from glomerular compartment of biopsy proven MCD or FSGS (NEPTUNE consortium) were analyzed to generate a Z-score for each gene for each patient. Individual gene Z-scores in the SH3BP2 signalosome were averaged to calculate the composite SH3BP2 Signalosome Score. IMPRes algorithm was used to visualize potential pathways for SH3BP2 gene. Clinical parameters from these subjects were used for statistical analysis to investigate outcome.

Results

Table shows significantly increased Z-score for the total SH3BP2 Signalosome Score in MCD (p=0.004) and in FSGS (p<0.001) compared to Control. SH3BP2 signalosome genes SH3BP2, VAV1, VAV2 and YWHAB were significantly increased in both MCD and FSGS. PLCG2 and YWHAG were also increased in FSGS. Downstream genes NFATc1 and MyD88 important in Sh3bp2-mediated signaling were also significantly upregulated in MCD and FSGS. IMPRes algorithm analysis suggests that SH3BP2 binds to PLCG2 and VAV2 for downstream signaling (Figure). SH3BP2 Signalosome Score was comparable between adults and children, and not associated with ESKD composite, ESKD and Remission.

Conclusion

SH3BP2 signaling complex is upregulated in biopsy from MCD and FSGS patients. SH3BP2-mediated immune activation needs comprehensive study using available mouse models with loss or gain of SH3BP2 function.

TABLE

FIGURE

Funding

  • NIDDK Support