Abstract: TH-PO0268
Sparsentan Reduces Glomerular IgA Deposition in gddY Mice and Suppresses Mesangial Autoantigen Exposure: Potential Role of cAMP
Session Information
- Glomerular Diseases: Cell Biology
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
- Mori, Kazuaki, Department of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Nihei, Yoshihito, Department of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
- Jenkinson, Celia P., Travere Therapeutics Inc., San Diego, California, United States
- Hendry, Bruce, Travere Therapeutics Inc., San Diego, California, United States
- Suzuki, Hitoshi, Department of Nephrology, Juntendo University Urayasu Hospital, Urayasu-shi, Chiba, Japan
- Suzuki, Yusuke, Department of Nephrology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan
Background
IgA nephropathy (IgAN) is characterized by mesangial IgA deposition, yet therapeutic targeting of this pathogenic process remains largely unexplored. Sparsentan (SP), a dual endothelin, angiotensin receptor antagonist has been shown to protect from glomerular IgA deposition in gddY mice and in human mesangial cells (HMCs). SP attenuates endothelin-1 (ET-1) and angiotensin II (Ang II) upregulation of the mesangial cell (MC)-surface autoantigen β2-spectrin, (Sci Adv 2023; Kidney Int Rep 2025). Here we explore the role of cAMP in β2-spectrin expression.
Methods
gddY mice, a spontaneous murine model of IgAN, received SP or control chow for 8 weeks for phenotypic analyses, and kidney single-cell RNA sequencing (scRNA-seq). HMCs were used to examine the regulation of cell-surface β2-spectrin expression by ET-1, Ang II, SP and dbcAMP (a cAMP analog).
Results
SP markedly reduced glomerular IgA deposition, with similar trends observed for C3 and IgG. Integrated kidney scRNA-seq analysis identified “response to cAMP” as an enriched gene ontology term from upregulated differentially-expressed genes in intraglomerular MC clusters from SP-treated gddY mice. In vitro analyses demonstrated that dbcAMP suppresses cell-surface β2-spectrin expression in HMCs (Figure 1).
Conclusion
SP reduces glomerular IgA deposition in gddY mice and upregulates cAMP-related gene expression pathways at the transcriptional level in MCs. In vitro β2-spectrin surface expression in HMCs was reduced by cAMP. Further studies will explore the role of cAMP signaling in the ET-1 and AngII regulation of β2-spectrin cell-surface expression in HMCs and its attenuation by SP. These studies begin to unravel potential mechanisms underlying mesangial autoantigen exposure proposed as a potentially targetable mechanism in for reducing glomerular IgA deposition in IgAN.
Five images/group; positive signal/total cell area. ± SEM from four independent experiments. One-way ANOVA; ****Padj < 0.0001.
Funding
- Commercial Support – Travere Therapeutics Inc.