title: Effect of Inhibition or Deletion of Neutral Endopeptidase on Neuropathic Endpoints in High Fat Fed/Low Dose Streptozotocin-Treated Mice.
abstract: 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.
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Yorek
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Alexander
authors.initials: A
authors.lastname: Obrosov
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Randy H
authors.initials: RH
authors.lastname: Kardon
authors.affiliation: From the Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA(MSY, RHK, MAY), Department of Internal Medicine, University of Iowa, Iowa City, IA(AO, MAY), Department of Pediatrics and Medicine, Harvard Medical School, Ina Sue Perlmutter Laboratory, Children's Hospital, Boston, MA(BL), Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA(RHK), Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Iowa City, IA(RHK, MAY) and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA(MAY).
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yorek
keywords: Candoxatril; Corneal nerves; Diabetes; Diabetic neuropathy; Neprilysin.; Neutral endopeptidase