Kidney Week

Abstract: TH-PO0425

Kidney Single-Cell and Peripheral Blood Immune Profiling Identify SH3BP2 as a Driver of Innate Immune Activation in Nephrotic Syndrome

Session Information

• Glomerular Diseases: Autoimmune Diseases
  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

• Srivastava, Tarak, Children's Mercy Kansas City, Kansas City, Missouri, United States

Tarak Srivastava, MD, FASN

• Pushel, Irina, Children's Mercy Kansas City, Kansas City, Missouri, United States

Irina Pushel, PhD

• Perry, John M., Children's Mercy Kansas City, Kansas City, Missouri, United States

John M. Perry, PhD

• Heruth, Daniel P., Children's Mercy Kansas City, Kansas City, Missouri, United States

Daniel P. Heruth, PhD

• Sharma, Mukut, Kansas City VA Medical Center, Kansas City, Missouri, United States

Mukut Sharma, PhD

Background

Immunopathogenesis of Nephrotic Syndrome remains unclear. We reported upregulated scaffold protein SH3BP2 signaling in glomerular transcriptomes of MCD and FSGS and enhanced innate immune activity in gain-of-function Sh3bp2^KI/KI mice with nephrotic syndrome features (JCI Insight 2024:e170055). We hypothesized that Sh3bp2 levels modulate innate immune profiles and gene expression in kidney and blood of Sh3bp2^KI/KI mice.

Methods

Sh3bp2^+/+, Sh3bp2^-/- and Sh3bp2^KI/KI (12 wk) underwent single-cell RNA sequencing (scRNA-seq) of kidneys (n=3/group), peripheral blood flow cytometry (n=5–6/group), and RNA sequencing of peripheral blood mononuclear cells (PBMCs; n=3/group for Sh3bp2^+/+ and Sh3bp2^KI/KI).

Results

scRNA-seq showed distinct cell populations across groups (Fig. 1a), with increased macrophages and reduced NKC in Sh3bp2^KI/KI mice (Fig. 1b). In Sh3bp2^KI/KI mice, the macrophage/monocyte compartment showed (1) emergence of Monocyte 3 (cluster 1) and Macrophage 1 (Mac1; cluster 5) populations, and (2) reduced macrophage (MonoDC, cluster 7) and dendritic cell (DC1, cluster 9; Fig. 1c–f) populations. NKC were also reduced (Fig. 1g–j).
PBMC RNA-seq from Sh3bp2^KI/KI mice showed upregulated cytokine and inflammatory pathways, and elevated cystatins type 1 and 2 specifically in Sh3bp2^KI/KI-specific Monocyte 3 cells in the scRNA-seq dataset (Fig. 2).
Flow cytometry confirmed increased myeloid populations (mainly monocytic) and reduced NKC in Sh3bp2^KI/KI mice. CD3+CD4-CD8- T cells increased, while B cells and innate lymphoid cells were unchanged.

Conclusion

Sh3bp2^KI/KI mice demonstrate heightened innate immune activation and identify Sh3bp2 as a driver of nephrotic syndrome through monocyte/macrophage polarization and decreased NKC.

Fig. 1

Fig. 2

Funding

• Other U.S. Government Support