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Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fruct...

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Autores principales: Andres-Hernando, Ana, Li, Nanxing, Cicerchi, Christina, Inaba, Shinichiro, Chen, Wei, Roncal-Jimenez, Carlos, Le, Myphuong T., Wempe, Michael F., Milagres, Tamara, Ishimoto, Takuji, Fini, Mehdi, Nakagawa, Takahiko, Johnson, Richard J., Lanaspa, Miguel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316807/
https://www.ncbi.nlm.nih.gov/pubmed/28194018
http://dx.doi.org/10.1038/ncomms14181
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author Andres-Hernando, Ana
Li, Nanxing
Cicerchi, Christina
Inaba, Shinichiro
Chen, Wei
Roncal-Jimenez, Carlos
Le, Myphuong T.
Wempe, Michael F.
Milagres, Tamara
Ishimoto, Takuji
Fini, Mehdi
Nakagawa, Takahiko
Johnson, Richard J.
Lanaspa, Miguel A.
author_facet Andres-Hernando, Ana
Li, Nanxing
Cicerchi, Christina
Inaba, Shinichiro
Chen, Wei
Roncal-Jimenez, Carlos
Le, Myphuong T.
Wempe, Michael F.
Milagres, Tamara
Ishimoto, Takuji
Fini, Mehdi
Nakagawa, Takahiko
Johnson, Richard J.
Lanaspa, Miguel A.
author_sort Andres-Hernando, Ana
collection PubMed
description Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease.
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spelling pubmed-53168072017-02-27 Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice Andres-Hernando, Ana Li, Nanxing Cicerchi, Christina Inaba, Shinichiro Chen, Wei Roncal-Jimenez, Carlos Le, Myphuong T. Wempe, Michael F. Milagres, Tamara Ishimoto, Takuji Fini, Mehdi Nakagawa, Takahiko Johnson, Richard J. Lanaspa, Miguel A. Nat Commun Article Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease. Nature Publishing Group 2017-02-13 /pmc/articles/PMC5316807/ /pubmed/28194018 http://dx.doi.org/10.1038/ncomms14181 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Andres-Hernando, Ana
Li, Nanxing
Cicerchi, Christina
Inaba, Shinichiro
Chen, Wei
Roncal-Jimenez, Carlos
Le, Myphuong T.
Wempe, Michael F.
Milagres, Tamara
Ishimoto, Takuji
Fini, Mehdi
Nakagawa, Takahiko
Johnson, Richard J.
Lanaspa, Miguel A.
Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title_full Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title_fullStr Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title_full_unstemmed Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title_short Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
title_sort protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316807/
https://www.ncbi.nlm.nih.gov/pubmed/28194018
http://dx.doi.org/10.1038/ncomms14181
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