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Background  Previous research demonstrated that small Rho GTPases, modulators of the actin cytoskeleton, are drivers of podocyte foot-process effacement in glomerular diseases, such as FSGS. However, a comprehensive understanding of the regulatory networks of small Rho GTPases in podocytes is lacking.    Methods  We conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped  in vivo , podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting  Srgap1 . To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy;  in situ  proximity ligation assays were used to determine the subcellular localization of the small GTPase-activating protein SRGAP1. We performed functional analysis of CRISPR/Cas9-generated  SRGAP1  knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics.    Results  We demonstrated SRGAP1 localization to podocyte foot processes  in vivo  and to cellular protrusions  in vitro .  Srgap1 fl/fl *Six2Cre  but not  Srgap1 fl/fl *hNPHS2Cre  knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of  Srgap1  by  hNPHS2Cre  resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore,  SRGAP1 -knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery  in vitro . Evaluation of a SRGAP1-dependent interactome revealed the involvement of SRGAP1 with protrusive and contractile actin networks. Analysis of glomerular biopsy specimens translated these findings toward human disease by displaying a pronounced redistribution of SRGAP1 in FSGS.    Conclusions  SRGAP1, a podocyte-specific RhoGAP, controls podocyte foot-process architecture by limiting the activity of protrusive, branched actin networks. Therefore, elucidating the complex regulatory small Rho GTPase affinity network points to novel targets for potentially precise intervention in glomerular diseases.

SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance