Kidney Week

Abstract: TH-PO0690

Studies on Transgenic Mice with Loss- or Gain-in-Function in the Sh3bp2 Gene Corroborate Importance of SH3BP2 Signalosome in Nephrotic Syndrome

Session Information

• Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
  November 06, 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

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

Tarak Srivastava, MD, FASN

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

John M Perry, PhD

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

Mukut Sharma, PhD

Background

Immunopathogenesis of Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) remains unclear. We reported upregulated scaffold protein SH3BP2 signaling in glomerular transcriptome in MCD and FSGS. Mice with a gain-in-function mutation (Sh3bp2^KI/KI) presented increased innate immune activity with features of nephrotic syndrome (JCI Insight 2024:e170055). Here, we compared the effect of Sh3bp2 gene deletion (Sh3bp2 ^-/-) vis-a-vis Sh3bp2^KI/KI mice.

Methods

Sh3bp2 ^+/+, Sh3bp2^-/- and Sh3bp2^KI/KI mice (4 and 12wks) were used to determine changes in albuminuria, serum albumin and creatinine (n=10-12/group), serum cytokines (Luminex Multiplex) and peripheral blood cells (flow cytometry) and podocyte ultrastructure (EM). Differences expressed at p<0.05.

Results

Bodyweight, but not kidney weight, was lower in Sh3bp2^KI/KI compared to Sh3bp2 ^+/+ or Sh3bp2 ^-/- at 4- and 12-wks, Albuminuria was higher in Sh3bp2^KI/KI compared to Sh3bp2 ^+/+ or Sh3bp2 ^-/- at 4- and 12-wks with hypoalbuminemia in Sh3bp2^KI/KI at 12wks (Fig. 1). Serum creatinine was comparable between groups. Sh3bp2^KI/KI mice showed decreased number of slits/length (EM).
Sh3bp2^KI/KI (12 wks) showed increased macrophages and double negative T-cells (CD3+CD4-CD8-) and decreased NKT cells and unchanged B-cells and innate lymphoid cells (IL).
Cytokines showing increase in Sh3bp2^KI/KI but not in Sh3bp2^-/- and Sh3bp2^+/+ mice were: TNFSF13B, Eotaxin, YKL-40, CXCL1, GDF-15, ICAM-1, IL-16, LDLR, TIMP-1, MCP-1, G-CSF, IL-1ra, MIP-1α, CXCL10, RANTES, IL-1β and TNFαa. LIX and MCSF increased in both Sh3bp2^KI/KI and Sh3bp2^-/- but not in Sh3bp2^+/+ mice.

Conclusion

Lack of changes in Sh3bp2^-/- mice supports previous findings suggesting the significance of increased SH3BP2 protein in immunopathogenesis of nephrotic syndrome.

The figure shows the albuminuria, serum albumin, serum creatinine, slits per length of GBM on EM and immune cells on flow cytometry.

Funding

• Other U.S. Government Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.202542ze6405