Document Type

Article

Publication Date

1-2025

Identifier

DOI: 10.1159/000542703; PMCID: PMC11842026

Abstract

BACKGROUND: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are major forms of nephrotic syndrome that remain difficult to treat. MCD and FSGS have distinct but also overlapping clinical, histological, metabolic, and molecular features. Effective use of immunosuppressive drugs, activated immune cells, altered cytokine profiles, and upregulated signaling pathways suggest a link between immune dysfunction and nephrotic syndrome, but the exact mechanism of immunopathogenesis is unclear. Immune dysfunction is an area of ongoing research for identifying novel molecular targets for treating nephrotic syndrome. However, the available animal models do not directly address the role of immune dysfunction in nephrotic syndrome.

SUMMARY: Genetic analysis indicates that heterogeneous genes related to the podocyte-specific proteins may indirectly cause damage to filtration barrier and influence the onset and progression of nephrotic syndrome. SH3BP2 protein regulates several pathways through its role as a scaffold for many signaling mediators and enzymes. SH3BP2 is expressed in immune as well as in nonimmune cells including podocytes. The role of SH3BP2 is discussed in the context of cells and molecules of adaptive and innate immune systems. Available information on the importance of SH3BP2 in diseases other than nephrotic syndrome and its role in the immunopathogenesis of human nephrotic syndrome are summarized. We outline the key features of a transgenic mouse strain with a gain-in-function mutation ((Sh3bp2 KI/KI ) as a potential model to study immunopathogenesis of nephrotic syndrome.

KEY MESSAGES: Non-receptor, non-catalytic proteins such as SH3BP2 are a novel group of proteins that regulate the innate and adaptive immune responses in nephrotic syndrome. New evidence suggests a critical role of SH3BP2 in immunopathogenesis of nephrotic syndrome. Our recent results demonstrate that transgenic mice ((Sh3bp2 KI/KI ) with a gain-in-function mutation will likely be a unique model to study immunopathogenesis of nephrotic syndrome.

Journal Title

Glomerular Dis

Volume

5

Issue

1

First Page

1

Last Page

12

PubMed ID

39991193

Keywords

Immune activation; Nephrotic syndrome; PLCG2 and VAV2; SH3BP2

Comments

Grants and funding

The work has been supported by funds from the Department of Defense (Peer Reviewed Medical Research Program [PRMRP] Investigator-Initiated Research Award, Award Number: HT9425-24-1-0235 [Srivastava]), NCATS 2UL1TR002366-07 (F3Y2-IAMI-Trailblazer), NephCure Kidney International – Pediatric Nephrology Research Consortium: Pediatric Glomerular Disease Accelerator Grant Program, Kiersznowski Family Charitable Trust, and Children’s Mercy-Kansas City (Srivastava) and funds from the Department of Defense (Peer Reviewed Medical Research Program [PRMRP] Investigator-Initiated Research Award, Award Number: HT9425-24-1-0236 [Sharma]) and the Midwest Veterans’ Biomedical Research Foundation and KCVA Medical Center, Kansas City, MO (Sharma). The funders had no role in the design, data collection, data analysis, and reporting of this study. This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Publisher's Link: https://karger.com/gdz/article/5/1/1/916254/Emerging-Role-of-SH3BP2-as-Regulator-of-Immune-and

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