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Abstract: FR-PO901

DNAJB9 Protein Accumulation in Fibrillary GN Is Not due to Local RNA Upregulation

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Nelson, Jonathan W., Oregon Health & Science University, Portland, Oregon, United States
  • Robinson, Bridget A., Oregon Health & Science University, Portland, Oregon, United States
  • Nice, Timothy J., Oregon Health & Science University, Portland, Oregon, United States
  • Woltjer, Randall, Oregon Health & Science University, Portland, Oregon, United States
  • Raess, Philipp W., Oregon Health & Science University, Portland, Oregon, United States
  • Gurley, Susan B., Oregon Health & Science University, Portland, Oregon, United States
  • Smith, Kelly D., University of Washington, Seattle, Washington, United States
  • Andeen, Nicole K., Oregon Health & Science University, Portland, Oregon, United States
Background

Fibrillary glomerulonephritis (FGN) is characterized by glomerular accumulations of haphazardly arranged fibrils and deposition of IgG with DNAJB9, a protein in the ER stress/unfolded protein response pathway (UPR). In this study, we sought to determine source of glomerular abundance of DNAJB9.

Methods

We evaluated formalin-fixed paraffin embedded kidney biopsies from patients with FGN (n=6), non-fibrillary glomerular disease (n=2 amyloidosis, n=3 cryoglobubulinemic gn, n=3 diabetic nephropathy) and normal controls (n=2). Confocal microscopy was performed on slides stained with a DNAJB9 RNA in situ hybridization probe and DAPI. Automated image analysis was performed and corroborated with DNAJB9 immunohistochemistry.

Results

By immunohistochemistry, FGN cases were DNAJB9-positive and non-FGN cases were DNAJB9-negative. DNAJB9 RNA signals were present in FGN, non-FGN glomerular disease, and normal controls; signals were identified in podocytes and mesangial regions as well as tubular, interstitial, and vascular tissue. There were no significant differences in glomerular DNAJB9 RNA signals (313 vs. 379, p=0.3), DNAJB9/DAPI ratios (2.25 vs. 3.3, p=0.3), or DNAJB9 signal intensity between FGN and non-FGN cases.

Conclusion

DNAJB9 RNA expression does not predict protein accumulation in FGN, suggesting that the pathogenesis of FGN is not dependent on local activation of the UPR. Our findings corroborate prior proteomic studies in which other components of the UPR pathway were not locally upregulated (PMID: 29097624), and provide contextual data to studies which identified increased levels of DNAJB9 protein in serum from patients with FGN (PMID: 31010480). This supports an alternate mechanism or circulating source for DNAJB9 accumulation in fibrillary GN.