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Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance
Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kin...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539221/ https://www.ncbi.nlm.nih.gov/pubmed/28824433 http://dx.doi.org/10.3389/fphar.2017.00509 |
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author | Haddad, Youssef Couture, Réjean |
author_facet | Haddad, Youssef Couture, Réjean |
author_sort | Haddad, Youssef |
collection | PubMed |
description | Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kininase 1 (carboxypeptidase M, CPM), the key enzyme involved in the biosynthesis of B1R agonists, could exert the same beneficial effects to B1R antagonism in insulin resistance. Male Sprague-Dawley rats were made insulin resistant with a drinking solution containing 10% D-glucose for a period of 9 weeks. Control rats received tap water. During the last week, kininase 1 was blocked with Mergetpa (1 mg kg(−1) twice daily, s.c.) and the impact was determined on insulin resistance (HOMA index), metabolic hormone levels, oxidative stress and the expression of several markers of inflammation by western blot and qRT-PCR. Glucose-fed rats displayed hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin resistance, hypertension, positive body weight gain, and enhanced expression of B1R, CPM, iNOS, and IL-1β in renal cortex, aorta and liver. Markers of oxidative stress (superoxide anion and nitrotyrosine expression) were also enhanced in aorta and renal cortex. Mergetpa reversed and normalized most of those alterations, but failed to affect leptin levels and hypertension. Pharmacological blockade of kininase 1 (CPM) exerted similar beneficial effects to a 1-week treatment with a B1R antagonist (SSR240612) or an iNOS inhibitor (1,400 W). These data reinforce the detrimental role of B1R in insulin resistance and recommend CPM as a new therapeutic target. |
format | Online Article Text |
id | pubmed-5539221 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55392212017-08-18 Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance Haddad, Youssef Couture, Réjean Front Pharmacol Pharmacology Kinin B1 receptor (B1R) contributes to insulin resistance, an early event in type 2 diabetes, through the upregulation and activation of the inducible form of nitric oxide synthase (iNOS), pro-inflammatory cytokines and the oxidative stress. This study addresses the hypothesis that inhibition of kininase 1 (carboxypeptidase M, CPM), the key enzyme involved in the biosynthesis of B1R agonists, could exert the same beneficial effects to B1R antagonism in insulin resistance. Male Sprague-Dawley rats were made insulin resistant with a drinking solution containing 10% D-glucose for a period of 9 weeks. Control rats received tap water. During the last week, kininase 1 was blocked with Mergetpa (1 mg kg(−1) twice daily, s.c.) and the impact was determined on insulin resistance (HOMA index), metabolic hormone levels, oxidative stress and the expression of several markers of inflammation by western blot and qRT-PCR. Glucose-fed rats displayed hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin resistance, hypertension, positive body weight gain, and enhanced expression of B1R, CPM, iNOS, and IL-1β in renal cortex, aorta and liver. Markers of oxidative stress (superoxide anion and nitrotyrosine expression) were also enhanced in aorta and renal cortex. Mergetpa reversed and normalized most of those alterations, but failed to affect leptin levels and hypertension. Pharmacological blockade of kininase 1 (CPM) exerted similar beneficial effects to a 1-week treatment with a B1R antagonist (SSR240612) or an iNOS inhibitor (1,400 W). These data reinforce the detrimental role of B1R in insulin resistance and recommend CPM as a new therapeutic target. Frontiers Media S.A. 2017-08-02 /pmc/articles/PMC5539221/ /pubmed/28824433 http://dx.doi.org/10.3389/fphar.2017.00509 Text en Copyright © 2017 Haddad and Couture. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Haddad, Youssef Couture, Réjean Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title | Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title_full | Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title_fullStr | Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title_full_unstemmed | Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title_short | Kininase 1 As a Preclinical Therapeutic Target for Kinin B(1) Receptor in Insulin Resistance |
title_sort | kininase 1 as a preclinical therapeutic target for kinin b(1) receptor in insulin resistance |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539221/ https://www.ncbi.nlm.nih.gov/pubmed/28824433 http://dx.doi.org/10.3389/fphar.2017.00509 |
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