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Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)

Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1–7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-sti...

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Autores principales: Brar, Gurkirat S., Barrow, Breanne M., Watson, Matthew, Griesbach, Ryan, Choung, Edwina, Welch, Andrew, Ruzsicska, Bela, Raleigh, Daniel P., Zraika, Sakeneh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521860/
https://www.ncbi.nlm.nih.gov/pubmed/28559246
http://dx.doi.org/10.2337/db16-1318
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author Brar, Gurkirat S.
Barrow, Breanne M.
Watson, Matthew
Griesbach, Ryan
Choung, Edwina
Welch, Andrew
Ruzsicska, Bela
Raleigh, Daniel P.
Zraika, Sakeneh
author_facet Brar, Gurkirat S.
Barrow, Breanne M.
Watson, Matthew
Griesbach, Ryan
Choung, Edwina
Welch, Andrew
Ruzsicska, Bela
Raleigh, Daniel P.
Zraika, Sakeneh
author_sort Brar, Gurkirat S.
collection PubMed
description Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1–7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1–7)–mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1–7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1–7) and neprilysin-derived degradation products angiotensin-(1–4), angiotensin-(5–7), and angiotensin-(3–4) failed to enhance GSIS. Conversely, angiotensin-(1–2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein–coupled receptor (GPCR) MasR, angiotensin-(1–2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1–7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1–7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1–7) compounds and neprilysin inhibitors as therapies for diabetes.
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spelling pubmed-55218602018-08-01 Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2) Brar, Gurkirat S. Barrow, Breanne M. Watson, Matthew Griesbach, Ryan Choung, Edwina Welch, Andrew Ruzsicska, Bela Raleigh, Daniel P. Zraika, Sakeneh Diabetes Islet Studies Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1–7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1–7)–mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1–7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1–7) and neprilysin-derived degradation products angiotensin-(1–4), angiotensin-(5–7), and angiotensin-(3–4) failed to enhance GSIS. Conversely, angiotensin-(1–2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein–coupled receptor (GPCR) MasR, angiotensin-(1–2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1–7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1–7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1–7) compounds and neprilysin inhibitors as therapies for diabetes. American Diabetes Association 2017-08 2017-05-30 /pmc/articles/PMC5521860/ /pubmed/28559246 http://dx.doi.org/10.2337/db16-1318 Text en © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Islet Studies
Brar, Gurkirat S.
Barrow, Breanne M.
Watson, Matthew
Griesbach, Ryan
Choung, Edwina
Welch, Andrew
Ruzsicska, Bela
Raleigh, Daniel P.
Zraika, Sakeneh
Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title_full Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title_fullStr Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title_full_unstemmed Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title_short Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
title_sort neprilysin is required for angiotensin-(1–7)’s ability to enhance insulin secretion via its proteolytic activity to generate angiotensin-(1–2)
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521860/
https://www.ncbi.nlm.nih.gov/pubmed/28559246
http://dx.doi.org/10.2337/db16-1318
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