Abstract: TH-PO0378
Extrarenal Detection of DNAJB9 in the Setting of Endoplasmic Reticulum Stress Supports a Two-Hit Model for Fibrillary Glomerulonephritis
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Smith, Kelly D., University of Washington School of Medicine, Seattle, Washington, United States
- Beirne, Emily, University of Washington School of Medicine, Seattle, Washington, United States
- Mills, Bre Alexis, University of Washington School of Medicine, Seattle, Washington, United States
- Akilesh, Shreeram, University of Washington School of Medicine, Seattle, Washington, United States
Background
Detection of DNAJB9 in the kidneys of patients with fibrillary glomerulonephritis (FGN) is a highly specific diagnostic marker of this disease. However, the role of DNAJB9 and how it contributes to the pathogenesis of FGN remains incompletely understood.
Methods
We identified surgical and autopsy specimens with high likelihoods of ER stress (hepatitis C viral hepatitis, metabolic dysfunction associated steatotic liver disease, and amyloidosis) and analyzed the expression and distribution of DNAJB9 and IgG using immunostaining. We also reviewed amyloid samples that we had previously typed using mass spectrometry for the codetection of DNAJB9, and confirmed expression and tissue distribution of DNAJB9 using immunohistochemistry.
Results
We detected DNAJB9 in the liver specimens of patients’ with viral hepatitis and ALECT2 (leukocyte chemotactic factor 2)-type amyloidosis. DNAJB9 was also detected in the sites with extrarenally produced amyloid proteins (liver, thyroid and bone marrow). Codeposition of IgG with DNAJB9 was only detected in the liver of one patient with hepatitis C viral hepatitis and FGN (Fig. 1).
Conclusion
Extrarenal deposition of DNAJB9 was detected in tissues with pathologies associated with ER stress responses. Codeposition of IgG in extrarenal sites was seen in one patient with concurrent FGN. These results support a two-hit model for FGN, where 1) ER stress induces the overproduction and release of DNAJB9, and 2) autoimmunity against DNAJB9 leads to immune complex accumulation and FGN. Identifying triggers of ER stress and other factors that influence autoimmunity to DNAJB9 may offer new targets for preventing and treating FGN.
Figure 1. Detection of DNAJB9 and IgG in the liver. A,B) Liver from a patient with active hepatitis C infection and FGN stained for DNAJB9 (A) and IgG (B) shows a sinusoidal staining for DNAJB9 and IgG. C,D) Liver from patient with ALECT2-type amyloidosis and no FGN stained for DNAJB9 (C) and IgG (D) shows a sinusoidal staining for DNAJB9 and no staining for IgG.