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Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model

Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the centr...

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Autores principales: Machida, Takashi, Takata, Fuyuko, Matsumoto, Junichi, Miyamura, Tomoyuki, Hirata, Ryosuke, Kimura, Ikuya, Kataoka, Yasufumi, Dohgu, Shinya, Yamauchi, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425209/
https://www.ncbi.nlm.nih.gov/pubmed/28489922
http://dx.doi.org/10.1371/journal.pone.0177447
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author Machida, Takashi
Takata, Fuyuko
Matsumoto, Junichi
Miyamura, Tomoyuki
Hirata, Ryosuke
Kimura, Ikuya
Kataoka, Yasufumi
Dohgu, Shinya
Yamauchi, Atsushi
author_facet Machida, Takashi
Takata, Fuyuko
Matsumoto, Junichi
Miyamura, Tomoyuki
Hirata, Ryosuke
Kimura, Ikuya
Kataoka, Yasufumi
Dohgu, Shinya
Yamauchi, Atsushi
author_sort Machida, Takashi
collection PubMed
description Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and (125)I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin–treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. (125)I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte–thrombin interaction may play a key role in causing BBB dysfunction in obesity-associated diabetes and represent a therapeutic target for its CNS complications.
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spelling pubmed-54252092017-05-15 Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model Machida, Takashi Takata, Fuyuko Matsumoto, Junichi Miyamura, Tomoyuki Hirata, Ryosuke Kimura, Ikuya Kataoka, Yasufumi Dohgu, Shinya Yamauchi, Atsushi PLoS One Research Article Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and (125)I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin–treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. (125)I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte–thrombin interaction may play a key role in causing BBB dysfunction in obesity-associated diabetes and represent a therapeutic target for its CNS complications. Public Library of Science 2017-05-10 /pmc/articles/PMC5425209/ /pubmed/28489922 http://dx.doi.org/10.1371/journal.pone.0177447 Text en © 2017 Machida et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Machida, Takashi
Takata, Fuyuko
Matsumoto, Junichi
Miyamura, Tomoyuki
Hirata, Ryosuke
Kimura, Ikuya
Kataoka, Yasufumi
Dohgu, Shinya
Yamauchi, Atsushi
Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title_full Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title_fullStr Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title_full_unstemmed Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title_short Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
title_sort contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425209/
https://www.ncbi.nlm.nih.gov/pubmed/28489922
http://dx.doi.org/10.1371/journal.pone.0177447
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