Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality

Abstract Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is abov...

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Autores principales:	Eva Maria Pastor-Arroyo, Josep M. Monné Rodriguez, Giovanni Pellegrini, Carla Bettoni, Moshe Levi, Nati Hernando, Carsten A. Wagner
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6cd0a69ddd7f4f809f809bc3e2f64873
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spelling	oai:doaj.org-article:6cd0a69ddd7f4f809f809bc3e2f648732021-12-02T15:51:13ZConstitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality10.1038/s41598-021-86874-z2045-2322https://doaj.org/article/6cd0a69ddd7f4f809f809bc3e2f648732021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86874-zhttps://doaj.org/toc/2045-2322Abstract Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is above physiological needs. While blocking intestinal absorption has been suggested as a therapeutic approach to prevent hyperphosphatemia, a complete picture regarding the identity and regulation of the mechanism(s) responsible for intestinal absorption of Pi is missing. The Na+/Pi cotransporter NaPi-IIb is a secondary active transporter encoded by the Slc34a2 gene. This transporter has a wide tissue distribution and within the intestinal tract is located at the apical membrane of epithelial cells. Based on mouse models deficient in NaPi-IIb, this cotransporter is assumed to mediate the bulk of active intestinal absorption of Pi. However, whether or not this is also applicable to humans is unknown, since human patients with inactivating mutations in SLC34A2 have not been reported to suffer from Pi depletion. Thus, mice may not be the most appropriate experimental model for the translation of intestinal Pi handling to humans. Here, we describe the generation of a rat model with Crispr/Cas-driven constitutive depletion of Slc34a2. Slc34a2 heterozygous rats were indistinguishable from wild type animals under standard dietary conditions as well as upon 3 days feeding on low Pi. However, unlike in humans, homozygosity resulted in perinatal lethality.Eva Maria Pastor-ArroyoJosep M. Monné RodriguezGiovanni PellegriniCarla BettoniMoshe LeviNati HernandoCarsten A. WagnerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eva Maria Pastor-Arroyo Josep M. Monné Rodriguez Giovanni Pellegrini Carla Bettoni Moshe Levi Nati Hernando Carsten A. Wagner Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
description	Abstract Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is above physiological needs. While blocking intestinal absorption has been suggested as a therapeutic approach to prevent hyperphosphatemia, a complete picture regarding the identity and regulation of the mechanism(s) responsible for intestinal absorption of Pi is missing. The Na+/Pi cotransporter NaPi-IIb is a secondary active transporter encoded by the Slc34a2 gene. This transporter has a wide tissue distribution and within the intestinal tract is located at the apical membrane of epithelial cells. Based on mouse models deficient in NaPi-IIb, this cotransporter is assumed to mediate the bulk of active intestinal absorption of Pi. However, whether or not this is also applicable to humans is unknown, since human patients with inactivating mutations in SLC34A2 have not been reported to suffer from Pi depletion. Thus, mice may not be the most appropriate experimental model for the translation of intestinal Pi handling to humans. Here, we describe the generation of a rat model with Crispr/Cas-driven constitutive depletion of Slc34a2. Slc34a2 heterozygous rats were indistinguishable from wild type animals under standard dietary conditions as well as upon 3 days feeding on low Pi. However, unlike in humans, homozygosity resulted in perinatal lethality.
format	article
author	Eva Maria Pastor-Arroyo Josep M. Monné Rodriguez Giovanni Pellegrini Carla Bettoni Moshe Levi Nati Hernando Carsten A. Wagner
author_facet	Eva Maria Pastor-Arroyo Josep M. Monné Rodriguez Giovanni Pellegrini Carla Bettoni Moshe Levi Nati Hernando Carsten A. Wagner
author_sort	Eva Maria Pastor-Arroyo
title	Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
title_short	Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
title_full	Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
title_fullStr	Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
title_full_unstemmed	Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality
title_sort	constitutive depletion of slc34a2/napi-iib in rats causes perinatal mortality
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6cd0a69ddd7f4f809f809bc3e2f64873
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Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality

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