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Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice

Previously we demonstrated that a vasopeptidase inhibitor of angiotensin converting enzyme and neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, improves neural function in diabetic rodent models. The purpose of this study was to determine whether inhibition or d...

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Autores principales: Yorek, Matthew S., Obrosov, Alexander, Lu, Bao, Gerard, Craig, Kardon, Randy H., Yorek, Mark A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714044/
https://www.ncbi.nlm.nih.gov/pubmed/27634964
http://dx.doi.org/10.1093/jnen/nlw083
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author Yorek, Matthew S.
Obrosov, Alexander
Lu, Bao
Gerard, Craig
Kardon, Randy H.
Yorek, Mark A.
author_facet Yorek, Matthew S.
Obrosov, Alexander
Lu, Bao
Gerard, Craig
Kardon, Randy H.
Yorek, Mark A.
author_sort Yorek, Matthew S.
collection PubMed
description Previously we demonstrated that a vasopeptidase inhibitor of angiotensin converting enzyme and neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, improves neural function in diabetic rodent models. The purpose of this study was to determine whether inhibition or deletion of NEP provides protection from neuropathy caused by diabetes with an emphasis on morphology of corneal nerves as a primary endpoint. Diabetes, modeling type 2, was induced in C57Bl/6J and NEP deficient mice through a combination of a high fat diet and streptozotocin. To inhibit NEP activity, diabetic C57Bl/6J mice were treated with candoxatril using a prevention or intervention protocol. Twelve weeks after the induction of diabetes in C57Bl/6J mice, the existence of diabetic neuropathy was determined through multiple endpoints including decrease in corneal nerves in the epithelium and sub-epithelium layer. Treatment of diabetic C57Bl/6J mice with candoxatril improved diabetic peripheral neuropathy and protected corneal nerve morphology with the prevention protocol being more efficacious than intervention. Unlike C57Bl/6J, mice deficient in NEP were protected from the development of neuropathologic alterations and loss of corneal nerves upon induction of diabetes. These studies suggest that NEP contributes to the development of diabetic neuropathy and may be a treatable target.
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spelling pubmed-77140442020-12-09 Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice Yorek, Matthew S. Obrosov, Alexander Lu, Bao Gerard, Craig Kardon, Randy H. Yorek, Mark A. J Neuropathol Exp Neurol Original Articles Previously we demonstrated that a vasopeptidase inhibitor of angiotensin converting enzyme and neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, improves neural function in diabetic rodent models. The purpose of this study was to determine whether inhibition or deletion of NEP provides protection from neuropathy caused by diabetes with an emphasis on morphology of corneal nerves as a primary endpoint. Diabetes, modeling type 2, was induced in C57Bl/6J and NEP deficient mice through a combination of a high fat diet and streptozotocin. To inhibit NEP activity, diabetic C57Bl/6J mice were treated with candoxatril using a prevention or intervention protocol. Twelve weeks after the induction of diabetes in C57Bl/6J mice, the existence of diabetic neuropathy was determined through multiple endpoints including decrease in corneal nerves in the epithelium and sub-epithelium layer. Treatment of diabetic C57Bl/6J mice with candoxatril improved diabetic peripheral neuropathy and protected corneal nerve morphology with the prevention protocol being more efficacious than intervention. Unlike C57Bl/6J, mice deficient in NEP were protected from the development of neuropathologic alterations and loss of corneal nerves upon induction of diabetes. These studies suggest that NEP contributes to the development of diabetic neuropathy and may be a treatable target. Oxford University Press 2016-11 2016-09-15 /pmc/articles/PMC7714044/ /pubmed/27634964 http://dx.doi.org/10.1093/jnen/nlw083 Text en 2016 American Association of Neuropathologists, Inc. This work is written by US Government employees and is in the public domain in the US. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Yorek, Matthew S.
Obrosov, Alexander
Lu, Bao
Gerard, Craig
Kardon, Randy H.
Yorek, Mark A.
Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title_full Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title_fullStr Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title_full_unstemmed Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title_short Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice
title_sort effect of inhibition or deletion of neutral endopeptidase on neuropathic endpoints in high fat fed/low dose streptozotocin-treated mice
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714044/
https://www.ncbi.nlm.nih.gov/pubmed/27634964
http://dx.doi.org/10.1093/jnen/nlw083
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