SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance

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. We conduc...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of the American Society of Nephrology Vol. 32; no. 3; pp. 563 - 579
Main Authors:	Rogg, Manuel, Maier, Jasmin I, Dotzauer, Robert, Artelt, Nadine, Kretz, Oliver, Helmstädter, Martin, Abed, Ahmed, Sammarco, Alena, Sigle, August, Sellung, Dominik, Dinse, Patrick, Reiche, Karoline, Yasuda-Yamahara, Mako, Biniossek, Martin L, Walz, Gerd, Werner, Martin, Endlich, Nicole, Schilling, Oliver, Huber, Tobias B, Schell, Christoph
Format:	Journal Article
Language:	English
Published:	United States American Society of Nephrology 01-03-2021
Subjects:	Actomyosin - metabolism Animals Basic Research Cell Surface Extensions - metabolism Cell Surface Extensions - ultrastructure Cells, Cultured Disease Models, Animal Female Glomerulosclerosis, Focal Segmental - etiology Glomerulosclerosis, Focal Segmental - metabolism Glomerulosclerosis, Focal Segmental - pathology GTPase-Activating Proteins - deficiency GTPase-Activating Proteins - genetics GTPase-Activating Proteins - metabolism Humans Integrins - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Nephrotic Syndrome - etiology Nephrotic Syndrome - metabolism Nephrotic Syndrome - pathology Podocytes - metabolism Podocytes - ultrastructure Protein Interaction Mapping Proteome Pseudopodia - metabolism Pseudopodia - ultrastructure rho GTP-Binding Proteins - metabolism Transcriptome Srgap1 cell adhesion RhoGAP cell signaling podocyte glomerular epithelial cells focal segmental glomerulosclerosis Rho GTPase nephrotic syndrome
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. We conducted an analysis of podocyte transcriptome and proteome datasets for Rho GTPases; mapped , podocyte-specific Rho GTPase affinity networks; and examined conditional knockout mice and murine disease models targeting . To evaluate podocyte foot-process morphology, we used super-resolution microscopy and electron microscopy; 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 knockout podocytes in two-dimensional and three-dimensional cultures and quantitative interaction proteomics. We demonstrated SRGAP1 localization to podocyte foot processes and to cellular protrusions . but not knockout mice developed an FSGS-like phenotype at adulthood. Podocyte-specific deletion of by resulted in increased susceptibility to doxorubicin-induced nephropathy. Detailed analysis demonstrated significant effacement of podocyte foot processes. Furthermore, -knockout podocytes showed excessive protrusion formation and disinhibition of the small Rho GTPase machinery . 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 T.B.H. and C.S. contributed equally to this work.
ISSN:	1046-6673 1533-3450
DOI:	10.1681/asn.2020081126