Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection

Shimada, Naoyuki; Matsuda, Jun; Asano-Matsuda, Kana; Tokuchi, Maho; Aoudjit, Lamine; Masztalerz, Agnieszka; Lemay, Serge; Takano, Tomoko; Isaka, Yoshitaka

doi:https://doi.org/10.1681/ASN.0000000614

Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection

Shimada, Naoyuki; Matsuda, Jun; Asano-Matsuda, Kana et al.

Journal of the American Society of Nephrology, 2025, 36(6), 1088-1104

アクセス数:387件（2025-09-12 08:42 集計）

固定URL: https://hdl.handle.net/11094/101416

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タイトル	Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection
著者	著者名 Shimada, Naoyuki
	NRID 1000010778260 1000010778260 researchmap permalink jun_matsuda jun_matsuda ORCID 0000-0003-1492-6157 0000-0003-1492-6157 著者名 Matsuda, Jun
	著者名 Asano-Matsuda, Kana
	著者名 Tokuchi, Maho
	著者名 Aoudjit, Lamine
	著者名 Masztalerz, Agnieszka
	著者名 Lemay, Serge
	著者名 Takano, Tomoko
	NRID 1000000379166 1000000379166 researchmap permalink isaka-handai3857 isaka-handai3857 Scopus Author ID 16207611100 16207611100 ORCID 0000-0002-0820-7167 0000-0002-0820-7167 著者名 Isaka, Yoshitaka
キーワード等	cell biology and structure
	glomerular disease
	glomerular epithelial cells
	podocyte
内容	Shimada N., Matsuda J., Asano-Matsuda K., et al. Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection. Journal of the American Society of Nephrology 36(6), 1088-1104 (2025); https://doi.org/10.1681/ASN.0000000614.
抄録	Background: Podocytes have an intricate structure featured by numerous actin-based projections called foot processes. Rho-family of small GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1), play important roles in actin cytoskeletal remodeling required for cell morphology and adhesion. We previously showed that Rac1 activation in podocytes causes foot process effacement and proteinuria, but the upstream and spatiotemporal regulatory mechanism directing Rac1 is largely unknown. Recently we identified the focal adhesion protein, GIT ArfGAP2 (GIT2) as one of the Rac1 interactors in human podocytes by proximity-dependent biotin identification (BioID) and proteomics. Methods: Systemic and podocyte-specific GIT2 knockout mice were generated and assessed for kidney phenotypes. Human podocytes with GIT2 knockdown and overexpression were established using lentiviral transduction and characterized. Results: GIT2 was enriched in glomeruli including podocytes in the mouse kidney. Gene deletion of Git2 in podocytes caused exacerbated proteinuria and foot process effacement when subjected to the minimal change disease model and the salt-sensitive hypertension model, which were improved by pharmacological inhibition of Rac1. In cultured podocytes, GIT2 knockdown resulted in Rac1-dependent cell spreading with marked lamellipodial protrusions, accelerated focal adhesion disassembly, and a shorter focal adhesion lifetime. In GIT2 knockdown podocytes, tyrosine phosphorylation of the focal adhesion protein, p130 Crk-associated substrate (Cas), was significantly increased, accompanied by impaired localization of the tyrosine phosphatase, PTP1B, to focal adhesions. These phenotypes observed in GIT2 knockdown podocytes were reversed by GIT2 overexpression. Conclusions: The results indicate that GIT2 facilitates translocation of PTP1B to focal adhesions where it dephosphorylates p130Cas, thereby suppressing local Rac1 activity and protecting against podocyte injury and proteinuria.
出版者	Wolters Kluwer Health
収録物名	Journal of the American Society of Nephrology
巻(号)	36(6)
ページ	1088-1104
刊行年月	2025-06
言語	英語
ハンドルURL	https://hdl.handle.net/11094/101416
PISSN	10466673
eISSN	15333450
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1681/ASN.0000000614
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Journal of the American Society of Nephrology. 2025, 36(6), p. 1088-1104
DC.title	Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection
DC.creator	Shimada, Naoyuki
	Matsuda, Jun
	Asano-Matsuda, Kana
	Tokuchi, Maho
	Aoudjit, Lamine
	Masztalerz, Agnieszka
	Lemay, Serge
	Takano, Tomoko
	Isaka, Yoshitaka
DC.publisher	Wolters Kluwer Health
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-06
DC.identifier	https://doi.org/10.1681/ASN.0000000614
DC.subject	cell biology and structure
	glomerular disease
	glomerular epithelial cells
	podocyte
DC.description	Shimada N., Matsuda J., Asano-Matsuda K., et al. Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection. Journal of the American Society of Nephrology 36(6), 1088-1104 (2025); https://doi.org/10.1681/ASN.0000000614.
DCTERMS.abstract	Background: Podocytes have an intricate structure featured by numerous actin-based projections called foot processes. Rho-family of small GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1), play important roles in actin cytoskeletal remodeling required for cell morphology and adhesion. We previously showed that Rac1 activation in podocytes causes foot process effacement and proteinuria, but the upstream and spatiotemporal regulatory mechanism directing Rac1 is largely unknown. Recently we identified the focal adhesion protein, GIT ArfGAP2 (GIT2) as one of the Rac1 interactors in human podocytes by proximity-dependent biotin identification (BioID) and proteomics. Methods: Systemic and podocyte-specific GIT2 knockout mice were generated and assessed for kidney phenotypes. Human podocytes with GIT2 knockdown and overexpression were established using lentiviral transduction and characterized. Results: GIT2 was enriched in glomeruli including podocytes in the mouse kidney. Gene deletion of Git2 in podocytes caused exacerbated proteinuria and foot process effacement when subjected to the minimal change disease model and the salt-sensitive hypertension model, which were improved by pharmacological inhibition of Rac1. In cultured podocytes, GIT2 knockdown resulted in Rac1-dependent cell spreading with marked lamellipodial protrusions, accelerated focal adhesion disassembly, and a shorter focal adhesion lifetime. In GIT2 knockdown podocytes, tyrosine phosphorylation of the focal adhesion protein, p130 Crk-associated substrate (Cas), was significantly increased, accompanied by impaired localization of the tyrosine phosphatase, PTP1B, to focal adhesions. These phenotypes observed in GIT2 knockdown podocytes were reversed by GIT2 overexpression. Conclusions: The results indicate that GIT2 facilitates translocation of PTP1B to focal adhesions where it dephosphorylates p130Cas, thereby suppressing local Rac1 activity and protecting against podocyte injury and proteinuria.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	101416
citation_title	Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection
citation_author	Shimada, Naoyuki
	Matsuda, Jun
	Asano-Matsuda, Kana
	Tokuchi, Maho
	Aoudjit, Lamine
	Masztalerz, Agnieszka
	Lemay, Serge
	Takano, Tomoko
	Isaka, Yoshitaka
citation_publisher	Wolters Kluwer Health
citation_language	英語
citation_date	2025-06
citation_journal_title	Journal of the American Society of Nephrology
citation_volume	36
citation_issue	6
citation_firstpage	1088
citation_lastpage	1104
citation_doi	https://doi.org/10.1681/ASN.0000000614
citation_public_url	https://hdl.handle.net/11094/101416

Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection

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