Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development

Okushima, Hiroki; Inoue, Kazunori; Imai, Atsuhiro; Matsumoto, Ayumi; Tamai, Natsune; Kunii, Masataka; Iriuchijima, Nobuhisa; Adam, Rüdiger; Al Rawahi, Yusriya; Al Sinani, Siham; Yamamoto, Takeshi; Mizui, Masayuki; Harada, Akihiro; Yanagita, Motoko; Isaka, Yoshitaka; Matsui, Isao

doi:https://doi.org/10.1016/j.kint.2025.08.027

Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development

Okushima, Hiroki; Inoue, Kazunori; Imai, Atsuhiro et al.

Kidney International, 2025, 108(6), 1088-1104

アクセス数:76件（2026-02-16 13:14 集計）

固定URL: https://hdl.handle.net/11094/103676

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タイトル	Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development
著者	NRID 1000070974632 1000070974632 ORCID 0000-0002-7953-2282 0000-0002-7953-2282 researchmap permalink oku_kidney oku_kidney 著者名 Okushima, Hiroki
	NRID 1000010631301 1000010631301 ORCID 0000-0002-7149-6651 0000-0002-7149-6651 researchmap permalink kznri kznri Scopus Author ID 55124465800 55124465800 著者名 Inoue, Kazunori
	ORCID 0009-0003-2136-0507 0009-0003-2136-0507 Scopus Author ID 58175687800 58175687800 著者名 Imai, Atsuhiro
	NRID 1000040794053 1000040794053 ORCID 0000-0002-2743-1439 0000-0002-2743-1439 Scopus Author ID 57200577037 57200577037 著者名 Matsumoto, Ayumi
	著者名 Tamai, Natsune
	NRID 1000080614768 1000080614768 ORCID 0000-0001-7222-7456 0000-0001-7222-7456 researchmap permalink kunimasa kunimasa Scopus Author ID 23985234600 23985234600 著者名 Kunii, Masataka
	NRID 1000010431719 1000010431719 著者名 Iriuchijima, Nobuhisa
	著者名 Adam, Rüdiger
	著者名 Al Rawahi, Yusriya
	著者名 Al Sinani, Siham
	NRID 1000020756994 1000020756994 ORCID 0009-0007-3817-0557 0009-0007-3817-0557 researchmap permalink tyamamoto-handai3857 tyamamoto-handai3857 Scopus Author ID 55628566248 55628566248 著者名 Yamamoto, Takeshi
	NRID 1000030423106 1000030423106 ORCID 0000-0003-2543-8108 0000-0003-2543-8108 researchmap permalink msmizui msmizui Scopus Author ID 8935909200 8935909200 著者名 Mizui, Masayuki
	NRID 1000040251441 1000040251441 researchmap permalink aharada aharada Scopus Author ID 7202253419 7202253419 著者名 Harada, Akihiro
	NRID 1000070378769 1000070378769 著者名 Yanagita, Motoko
	NRID 1000000379166 1000000379166 ORCID 0000-0002-0820-7167 0000-0002-0820-7167 researchmap permalink isaka-handai3857 isaka-handai3857 Scopus Author ID 16207611100 16207611100 著者名 Isaka, Yoshitaka
	NRID 1000060456986 1000060456986 ORCID 0000-0001-8378-6130 0000-0001-8378-6130 researchmap permalink matsui-handai3857 matsui-handai3857 Scopus Author ID 24488796300 24488796300 著者名 Matsui, Isao
キーワード等	apical membrane
	Fanconi syndrome
	microvillus inclusion disease
	polarity
	proximal tubules
	syntaxin 3
内容	Okushima H., Inoue K., Imai A., et al. Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development. Kidney International 108, 1088 (2025); https://doi.org/10.1016/j.kint.2025.08.027.
抄録	Introduction: Epithelial cell polarity is crucial for the proper functioning of various organs, including the kidneys. Syntaxin 3, a key molecule in membrane-vesicle fusion, is localized in the apical membrane of proximal tubule epithelial cells (PTECs). Although in vitro studies using the other type of epithelial cells besides PTECs have shown the role of syntaxin 3 in regulating apical membrane integrity, its function in epithelial cells in vivo, particularly in PTECs, remains undefined. Methods: We analyzed the renal phenotypes of a newly generated PTEC-specific Stx3 knockout mice (Stx3-cKO) and examined urine samples from patients with microvillus inclusion disease (MVID) carrying STX3 mutations. Results: Stx3-cKO mice exhibited features of Fanconi syndrome, including increased urinary excretion of phosphorus, glucose, amino acids, and low-molecular-weight proteins. Patients with MVID showed similar urinary abnormalities. The mice exhibited brush border atrophy and vesicle transport stagnation, as evidenced by electron microscopy, and increased subapical localization of trafficking markers, Rab11 and vesicle-associated membrane protein 8. Key transporters and receptors including sodium-dependent phosphate cotransporter type 2a, sodium-glucose cotransporter 2, a protein related to the neutral and basic amino acid transport protein rBAT, and megalin showed mislocalization and/or altered expression. Syntaxin 3 deficiency disrupted the apical expression of ezrin, a crucial protein that links the actin cytoskeleton to the plasma membrane. Both receptor-mediated and fluid-phase endocytosis were impaired in Stx3-cKO mice. Conclusions: Our results highlight the critical role of syntaxin 3 in maintaining PTEC function and apical polarity, providing new insights into the kidney manifestations of MVID and the molecular mechanisms underlying Fanconi syndrome.
出版者	Elsevier B.V.
収録物名	Kidney International
巻(号)	108(6)
ページ	1088-1104
刊行年月	2025-09-29
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103676
PISSN	00852538
eISSN	15231755
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1016/j.kint.2025.08.027
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 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	Kidney International. 2025, 108(6), p. 1088-1104
DC.title	Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development
DC.creator	Okushima, Hiroki
	Inoue, Kazunori
	Imai, Atsuhiro
	Matsumoto, Ayumi
	Tamai, Natsune
	Kunii, Masataka
	Iriuchijima, Nobuhisa
	Adam, Rüdiger
	Al Rawahi, Yusriya
	Al Sinani, Siham
	Yamamoto, Takeshi
	Mizui, Masayuki
	Harada, Akihiro
	Yanagita, Motoko
	Isaka, Yoshitaka
	Matsui, Isao
DC.publisher	Elsevier B.V.
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-09-29
DC.identifier	https://doi.org/10.1016/j.kint.2025.08.027
DC.subject	apical membrane
	Fanconi syndrome
	microvillus inclusion disease
	polarity
	proximal tubules
	syntaxin 3
DC.description	Okushima H., Inoue K., Imai A., et al. Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development. Kidney International 108, 1088 (2025); https://doi.org/10.1016/j.kint.2025.08.027.
DCTERMS.abstract	Introduction: Epithelial cell polarity is crucial for the proper functioning of various organs, including the kidneys. Syntaxin 3, a key molecule in membrane-vesicle fusion, is localized in the apical membrane of proximal tubule epithelial cells (PTECs). Although in vitro studies using the other type of epithelial cells besides PTECs have shown the role of syntaxin 3 in regulating apical membrane integrity, its function in epithelial cells in vivo, particularly in PTECs, remains undefined. Methods: We analyzed the renal phenotypes of a newly generated PTEC-specific Stx3 knockout mice (Stx3-cKO) and examined urine samples from patients with microvillus inclusion disease (MVID) carrying STX3 mutations. Results: Stx3-cKO mice exhibited features of Fanconi syndrome, including increased urinary excretion of phosphorus, glucose, amino acids, and low-molecular-weight proteins. Patients with MVID showed similar urinary abnormalities. The mice exhibited brush border atrophy and vesicle transport stagnation, as evidenced by electron microscopy, and increased subapical localization of trafficking markers, Rab11 and vesicle-associated membrane protein 8. Key transporters and receptors including sodium-dependent phosphate cotransporter type 2a, sodium-glucose cotransporter 2, a protein related to the neutral and basic amino acid transport protein rBAT, and megalin showed mislocalization and/or altered expression. Syntaxin 3 deficiency disrupted the apical expression of ezrin, a crucial protein that links the actin cytoskeleton to the plasma membrane. Both receptor-mediated and fluid-phase endocytosis were impaired in Stx3-cKO mice. Conclusions: Our results highlight the critical role of syntaxin 3 in maintaining PTEC function and apical polarity, providing new insights into the kidney manifestations of MVID and the molecular mechanisms underlying Fanconi syndrome.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	103676
citation_title	Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development
citation_author	Okushima, Hiroki
	Inoue, Kazunori
	Imai, Atsuhiro
	Matsumoto, Ayumi
	Tamai, Natsune
	Kunii, Masataka
	Iriuchijima, Nobuhisa
	Adam, Rüdiger
	Al Rawahi, Yusriya
	Al Sinani, Siham
	Yamamoto, Takeshi
	Mizui, Masayuki
	Harada, Akihiro
	Yanagita, Motoko
	Isaka, Yoshitaka
	Matsui, Isao
citation_publisher	Elsevier B.V.
citation_language	英語
citation_date	2025-09-29
citation_journal_title	Kidney International
citation_volume	108
citation_issue	6
citation_firstpage	1088
citation_lastpage	1104
citation_doi	https://doi.org/10.1016/j.kint.2025.08.027
citation_public_url	https://hdl.handle.net/11094/103676

Syntaxin 3 regulates apical membrane integrity in proximal tubule epithelial cells and prevents Fanconi syndrome development

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