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Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy

BACKGROUND: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN...

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Autores principales: Fukami, Kei, Yamagishi, Sho-ichi, Coughlan, Melinda T, Harcourt, Brooke E, Kantharidis, Phillip, Thallas-Bonke, Vicki, Okuda, Seiya, Cooper, Mark E, Forbes, Josephine M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138378/
https://www.ncbi.nlm.nih.gov/pubmed/25143788
http://dx.doi.org/10.1186/1758-5996-6-86
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author Fukami, Kei
Yamagishi, Sho-ichi
Coughlan, Melinda T
Harcourt, Brooke E
Kantharidis, Phillip
Thallas-Bonke, Vicki
Okuda, Seiya
Cooper, Mark E
Forbes, Josephine M
author_facet Fukami, Kei
Yamagishi, Sho-ichi
Coughlan, Melinda T
Harcourt, Brooke E
Kantharidis, Phillip
Thallas-Bonke, Vicki
Okuda, Seiya
Cooper, Mark E
Forbes, Josephine M
author_sort Fukami, Kei
collection PubMed
description BACKGROUND: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs). METHODS: Experimental diabetes was induced in 6-week-old male Sprague–Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10(-7) M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor. RESULTS: AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082. CONCLUSIONS: Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2.
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spelling pubmed-41383782014-08-21 Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy Fukami, Kei Yamagishi, Sho-ichi Coughlan, Melinda T Harcourt, Brooke E Kantharidis, Phillip Thallas-Bonke, Vicki Okuda, Seiya Cooper, Mark E Forbes, Josephine M Diabetol Metab Syndr Research BACKGROUND: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs). METHODS: Experimental diabetes was induced in 6-week-old male Sprague–Dawley (SD) rats by intravenous injection of STZ. Diabetic rats received ramipril (3 mg/kg body weight/day) or vehicle for 32 weeks. AGE-modified rat serum albumin (AGE-RSA) or RSA was intraperitoneally administrated to 6-week-old male SD rats for 16 weeks. RPTCs were stimulated with 100 μg/ml AGE-modified bovine serum albumin (AGE-BSA) or BSA in the presence or absence of 10(-7) M ramiprilat, an inhibitor of angiotensin-converting enzyme or 100 nM BAY11-7082, an IκB-α phosphorylation inhibitor. RESULTS: AGE and RAGE expression levels and MMP-2 activity in the tubules of diabetic rats was significantly increased in association with increased albuminuria, all of which were blocked by ramipril. AGE infusion induced tubular MMP-2 activation and RAGE gene expression in SD rats. Ramiprilat or BAY11-7082 inhibited the AGE-induced MMP-2 activation or reactive oxygen species generation in RPTCs. Angiotensin II increased MMP-2 gene expression in RPTCs, which was blocked by BAY11-7082. CONCLUSIONS: Our present study suggests the involvement of AGE-RAGE-induced, RAS-mediated MMP-2 activation in experimental DN. Blockade of AGE-RAGE axis by ramipril may protect against DN partly via suppression of MMP-2. BioMed Central 2014-08-13 /pmc/articles/PMC4138378/ /pubmed/25143788 http://dx.doi.org/10.1186/1758-5996-6-86 Text en © Fukami et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Fukami, Kei
Yamagishi, Sho-ichi
Coughlan, Melinda T
Harcourt, Brooke E
Kantharidis, Phillip
Thallas-Bonke, Vicki
Okuda, Seiya
Cooper, Mark E
Forbes, Josephine M
Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title_full Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title_fullStr Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title_full_unstemmed Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title_short Ramipril inhibits AGE-RAGE-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
title_sort ramipril inhibits age-rage-induced matrix metalloproteinase-2 activation in experimental diabetic nephropathy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138378/
https://www.ncbi.nlm.nih.gov/pubmed/25143788
http://dx.doi.org/10.1186/1758-5996-6-86
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