Abstract: SA-PO0748
Mechanistic Study of Monoclonal Cryoglobulinemic Glomerulonephritis: Insights from Single-Cell Data and Mouse Models
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Dai, Dao-Fu, Johns Hopkins Medicine, Baltimore, Maryland, United States
- Yoshida, Teruhiko, University of Tokyo, Tokyo, Japan
- Rosenberg, Avi Z., Johns Hopkins Medicine, Baltimore, Maryland, United States
- Latt, Khun Zaw, University of Michigan, Ann Arbor, Michigan, United States
Background
Cryoglobulinemic glomerulonephritis (Cryo-GN) is characterized by intracapillary and capillary wall depositions of cryoglobulin. The mechanisms leading to Cryo-GN are unclear, particularly in the context of monoclonal gammopathy of renal significance.
Methods
We use multiple-myeloma mice carrying a human IL-6 Tg driven by the major histocompatibility complex H2-Ld promoter (IL-6) with concomitant Tg of i-Myc with deregulated expression of the Myc oncogene and enhancers in the IgH locus (designated IL6/Myc). The majority of these mice developed monoclonal Cryo-GN with IgM.kappa deposits. Using single-nuclear RNA sequencing, we characterize the single-cell transcriptome in glomerular cells to elucidate the pathogenic mechanisms of Cryo-GN. Using a second mouse model of marginal zone lymphoma, we confirm the significance of notch and NF-KB in the pathogenesis of monoclonal Cryo-GN
Results
In IL6/i-Myc mice, cell typing analysis by canonical marker genes shows a substantial increase in macrophages and T-cells, with a decreased fraction of podocytes. Differential expression analysis reveals several Cryo-GN signature genes that are significantly upregulated more than 2-fold in glomerular endothelial cells and macrophages, such as Fkbp5, Zbtb16, Notch, etc. Fkbp5 is a co-chaperone of the Hsp90 complex that interacts with glucocorticoid receptors (GR). It modulates stress response and interacts with the inhibitor of nuclear factor kappa-B (NF-κB) kinase subunit alpha (IKK-α), enhancing NF-κB signaling to promote inflammation (as seen in Cryo-GN). To test the role of NF-KB and Notch, we examined the kidneys from mice overexpressing Notch and NF-KB driven by CD19 Cre, which developed B-cell marginal zone lymphoma. These mice developed mesangioproliferative lesions around 3 months, monoclonal cryoGN (IgM.kappa) around 6-7 months, then progressed to MPGN pattern around 10 months, confirming the role of Notch and NF-KB in the pathogenesis of Cryo-GN.
Conclusion
We elucidate the mechanistic insights into the molecular pathogenesis of monoclonal Cryo-GN. Our studies suggest the critical roles of glomerular endothelial inflammatory pathways, via FKBP5 regulation of NF-KB and the downstream inflammation, as well as Notch signaling.
Funding
- NIDDK Support