Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death

Abstract Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are current...

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Autores principales:	Amy L. Clark, Kohsuke Kanekura, Zeno Lavagnino, Larry D. Spears, Damien Abreu, Jana Mahadevan, Takuya Yagi, Clay F. Semenkovich, David W. Piston, Fumihiko Urano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/be8e2bac311c4815b5a158b712b3a6a3
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spelling	oai:doaj.org-article:be8e2bac311c4815b5a158b712b3a6a32021-12-02T12:32:52ZTargeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death10.1038/s41598-017-05935-42045-2322https://doaj.org/article/be8e2bac311c4815b5a158b712b3a6a32017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05935-4https://doaj.org/toc/2045-2322Abstract Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.Amy L. ClarkKohsuke KanekuraZeno LavagninoLarry D. SpearsDamien AbreuJana MahadevanTakuya YagiClay F. SemenkovichDavid W. PistonFumihiko UranoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amy L. Clark Kohsuke Kanekura Zeno Lavagnino Larry D. Spears Damien Abreu Jana Mahadevan Takuya Yagi Clay F. Semenkovich David W. Piston Fumihiko Urano Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
description	Abstract Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.
format	article
author	Amy L. Clark Kohsuke Kanekura Zeno Lavagnino Larry D. Spears Damien Abreu Jana Mahadevan Takuya Yagi Clay F. Semenkovich David W. Piston Fumihiko Urano
author_facet	Amy L. Clark Kohsuke Kanekura Zeno Lavagnino Larry D. Spears Damien Abreu Jana Mahadevan Takuya Yagi Clay F. Semenkovich David W. Piston Fumihiko Urano
author_sort	Amy L. Clark
title	Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
title_short	Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
title_full	Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
title_fullStr	Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
title_full_unstemmed	Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death
title_sort	targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/be8e2bac311c4815b5a158b712b3a6a3
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Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death

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