| Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy? | |
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MedLine Citation:
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PMID: 17110423 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Blockade of advanced glycation end product (AGE) accumulation with alagebrium with concomitant angiotensin converting enzyme inhibition was tested for effects on renal function and on other postulated mediators of diabetic renal disease including the renin-angiotensin system, AGEs, mitochondrial and cytosolic oxidative stress, and intracellular signaling molecules. Sprague Dawley rats were rendered diabetic with streptozocin and followed consecutively for 32 wk with nondiabetic controls. Groups were treated with ramipril (1 mg/kg.d; wk 0-32); alagebrium (10 mg/kg.d; wk 16-32); or a combination of both. Although individual treatments had significant effects on albuminuria, no further improvements were seen with combination therapy. Changes in urinary vascular endothelial growth factor excretion mirrored those seen in albuminuria. Diabetes was associated with suppression of circulating angiotensin II in the context of increased circulating and renal levels of the AGE, carboxymethyllysine. All treatments attenuated circulating but not renal carboxymethyllysine levels. The renal gene expression of AGE receptor 1 and soluble receptor for advanced glycation end products were markedly reduced by diabetes and normalized with alagebrium. Diabetes induced renal mitochondrial oxidative stress, which was reduced with alagebrium. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous protein kinase C activity in diabetes were attenuated by all treatments, whereas diabetes-associated increases in nuclear factor-kappaB p65 translocation remained unaltered by any therapy. It is evident that renin-angiotensin system blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in diabetic nephropathy. |
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Authors:
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Melinda T Coughlan; Vicki Thallas-Bonke; Josefa Pete; David M Long; Anna Gasser; David C K Tong; Maryann Arnstein; Suzanne R Thorpe; Mark E Cooper; Josephine M Forbes |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-11-16 |
Journal Detail:
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Title: Endocrinology Volume: 148 ISSN: 0013-7227 ISO Abbreviation: Endocrinology Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-17 Completed Date: 2007-02-27 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 886-95 Citation Subset: AIM; IM |
Affiliation:
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Albert Einstein Juvenile Diabetes Research Foundation Centre for Diabetes Complications, Wynn Domain, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. melinda.coughlan@baker.edu.au |
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin-Converting Enzyme Inhibitors
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therapeutic use* Animals Cytosol / metabolism Diabetes Mellitus, Experimental / drug therapy*, metabolism, physiopathology Drug Synergism Drug Therapy, Combination Enzyme Activation / drug effects Glycosylation End Products, Advanced / antagonists & inhibitors*, chemistry Kidney / drug effects, metabolism, physiopathology Lysine / analogs & derivatives, blood Male Mitochondria / metabolism NF-kappa B / metabolism Oxidative Stress / drug effects Protein Kinase C / metabolism Ramipril / therapeutic use* Rats Rats, Sprague-Dawley Receptors, Immunologic / metabolism Renin-Angiotensin System Superoxide Dismutase / metabolism Thiazoles / therapeutic use* Vascular Endothelial Growth Factor A / urine |
| Grant Support | |
ID/Acronym/Agency:
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NIDDK-19971//PHS HHS |
| Chemical | |
Reg. No./Substance:
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0/ALT 711; 0/Angiotensin-Converting Enzyme Inhibitors; 0/Glycosylation End Products, Advanced; 0/NF-kappa B; 0/Receptors, Immunologic; 0/Thiazoles; 0/Vascular Endothelial Growth Factor A; 0/advanced glycosylation end-product receptor; 56-87-1/Lysine; 5746-04-3/N(6)-carboxymethyllysine; 87333-19-5/Ramipril; EC 1.15.1.1/Superoxide Dismutase; EC 2.7.11.13/Protein Kinase C |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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