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

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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 (Sh3bp2KI/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 Sh3bp2KI/KI mice. Methods: Sh3bp2 +/+, Sh3bp2-/- and Sh3bp2KI/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 Sh3bp2KI/KIcompared to Sh3bp2 +/+ or Sh3bp2 -/- at 4- and 12-wks, Albuminuria was higher in Sh3bp2KI/KIcompared to Sh3bp2 +/+ or Sh3bp2 -/- at 4- and 12-wks with hypoalbuminemia in Sh3bp2KI/KIat 12wks (Fig. 1). Serum creatinine was comparable between groups. Sh3bp2KI/KI mice showed decreased number of slits/length (EM). Sh3bp2KI/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 Sh3bp2KI/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 Sh3bp2KI/KIand 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. Funding: Other U.S. Government SupportThe figure shows the albuminuria, serum albumin, serum creatinine, slits per length of GBM on EM and immune cells on flow cytometry.

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