Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells

Abstract Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived ind...

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Autores principales:	Tomoko Ohmori, Shankhajit De, Shunsuke Tanigawa, Koichiro Miike, Mazharul Islam, Minami Soga, Takumi Era, Shinichi Shiona, Koichi Nakanishi, Hitoshi Nakazato, Ryuichi Nishinakamura
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c2b456edae140c986775a691c1c186b
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spelling	oai:doaj.org-article:3c2b456edae140c986775a691c1c186b2021-12-02T14:03:58ZImpaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells10.1038/s41598-021-83501-92045-2322https://doaj.org/article/3c2b456edae140c986775a691c1c186b2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83501-9https://doaj.org/toc/2045-2322Abstract Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) with an NPHS1 missense mutation (E725D). However, the mechanisms underlying the disease may vary depending on the mutations involved, and thus generation of iPSCs from multiple patients is warranted. Here we established iPSCs from two additional patients with different NPHS1 mutations and examined the podocyte abnormalities in kidney organoids derived from these cells. One patient had truncating mutations, and NEPHRIN was undetectable in the resulting organoids. The other patient had a missense mutation (R460Q), and the mutant NEPHRIN in the organoids failed to accumulate on the podocyte surface to form SD precursors. However, the same mutant protein behaved normally when overexpressed in heterologous cells, suggesting that NEPHRIN localization is cell context-dependent. The localization of another SD-associated protein, PODOCIN, was impaired in both types of mutant organoids in a cell domain-specific manner. Thus, the new iPSC lines and resultant kidney organoids will be useful resources for dissecting the disease mechanisms, as well as for drug development for therapies.Tomoko OhmoriShankhajit DeShunsuke TanigawaKoichiro MiikeMazharul IslamMinami SogaTakumi EraShinichi ShionaKoichi NakanishiHitoshi NakazatoRyuichi NishinakamuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tomoko Ohmori Shankhajit De Shunsuke Tanigawa Koichiro Miike Mazharul Islam Minami Soga Takumi Era Shinichi Shiona Koichi Nakanishi Hitoshi Nakazato Ryuichi Nishinakamura Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
description	Abstract Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) with an NPHS1 missense mutation (E725D). However, the mechanisms underlying the disease may vary depending on the mutations involved, and thus generation of iPSCs from multiple patients is warranted. Here we established iPSCs from two additional patients with different NPHS1 mutations and examined the podocyte abnormalities in kidney organoids derived from these cells. One patient had truncating mutations, and NEPHRIN was undetectable in the resulting organoids. The other patient had a missense mutation (R460Q), and the mutant NEPHRIN in the organoids failed to accumulate on the podocyte surface to form SD precursors. However, the same mutant protein behaved normally when overexpressed in heterologous cells, suggesting that NEPHRIN localization is cell context-dependent. The localization of another SD-associated protein, PODOCIN, was impaired in both types of mutant organoids in a cell domain-specific manner. Thus, the new iPSC lines and resultant kidney organoids will be useful resources for dissecting the disease mechanisms, as well as for drug development for therapies.
format	article
author	Tomoko Ohmori Shankhajit De Shunsuke Tanigawa Koichiro Miike Mazharul Islam Minami Soga Takumi Era Shinichi Shiona Koichi Nakanishi Hitoshi Nakazato Ryuichi Nishinakamura
author_facet	Tomoko Ohmori Shankhajit De Shunsuke Tanigawa Koichiro Miike Mazharul Islam Minami Soga Takumi Era Shinichi Shiona Koichi Nakanishi Hitoshi Nakazato Ryuichi Nishinakamura
author_sort	Tomoko Ohmori
title	Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
title_short	Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
title_full	Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
title_fullStr	Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
title_full_unstemmed	Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells
title_sort	impaired nephrin localization in kidney organoids derived from nephrotic patient ips cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3c2b456edae140c986775a691c1c186b
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Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells

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