Research ExplorerPublicationsSRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot ...

SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance

Standard

SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance. / 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.

In: J AM SOC NEPHROL, Vol. 32, No. 3, 03.2021, p. 563-579.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rogg, M, Maier, JI, Dotzauer, R, Artelt, N, Kretz, O, Helmstädter, M, Abed, A, Sammarco, A, Sigle, A, Sellung, D, Dinse, P, Reiche, K, Yasuda-Yamahara, M, Biniossek, ML, Walz, G, Werner, M, Endlich, N, Schilling, O, Huber, TB & Schell, C 2021, 'SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance', J AM SOC NEPHROL, vol. 32, no. 3, pp. 563-579. https://doi.org/10.1681/ASN.2020081126

APA

Rogg, M., Maier, J. I., Dotzauer, R., Artelt, N., Kretz, O., Helmstädter, M., Abed, A., Sammarco, A., Sigle, A., Sellung, D., Dinse, P., Reiche, K., Yasuda-Yamahara, M., Biniossek, M. L., Walz, G., Werner, M., Endlich, N., Schilling, O., Huber, T. B., & Schell, C. (2021). SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance. J AM SOC NEPHROL, 32(3), 563-579. https://doi.org/10.1681/ASN.2020081126

Vancouver

Rogg M, Maier JI, Dotzauer R, Artelt N, Kretz O, Helmstädter M et al. SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance. J AM SOC NEPHROL. 2021 Mar;32(3):563-579. https://doi.org/10.1681/ASN.2020081126

Bibtex

@article{e32c8f47404a4831afc0166556d49478,
title = "SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance",
abstract = "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. Srgap1fl/fl*Six2Cre but not Srgap1fl/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.",
author = "Manuel Rogg and Maier, {Jasmin I} and Robert Dotzauer and Nadine Artelt and Oliver Kretz and Martin Helmst{\"a}dter and Ahmed Abed and Alena Sammarco and August Sigle and Dominik Sellung and Patrick Dinse and Karoline Reiche and Mako Yasuda-Yamahara and Biniossek, {Martin L} and Gerd Walz and Martin Werner and Nicole Endlich and Oliver Schilling and Huber, {Tobias B} and Christoph Schell",
note = "Copyright {\textcopyright} 2021 by the American Society of Nephrology.",
year = "2021",
month = mar,
doi = "10.1681/ASN.2020081126",
language = "English",
volume = "32",
pages = "563--579",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "3",

}

RIS

TY - JOUR

T1 - SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance

AU - Rogg, Manuel

AU - Maier, Jasmin I

AU - Dotzauer, Robert

AU - Artelt, Nadine

AU - Kretz, Oliver

AU - Helmstädter, Martin

AU - Abed, Ahmed

AU - Sammarco, Alena

AU - Sigle, August

AU - Sellung, Dominik

AU - Dinse, Patrick

AU - Reiche, Karoline

AU - Yasuda-Yamahara, Mako

AU - Biniossek, Martin L

AU - Walz, Gerd

AU - Werner, Martin

AU - Endlich, Nicole

AU - Schilling, Oliver

AU - Huber, Tobias B

AU - Schell, Christoph

N1 - Copyright © 2021 by the American Society of Nephrology.

PY - 2021/3

Y1 - 2021/3

N2 - 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. Srgap1fl/fl*Six2Cre but not Srgap1fl/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.

AB - 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. Srgap1fl/fl*Six2Cre but not Srgap1fl/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.

U2 - 10.1681/ASN.2020081126

DO - 10.1681/ASN.2020081126

M3 - SCORING: Journal article

C2 - 33514561

VL - 32

SP - 563

EP - 579

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 3

ER -