title: Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy?
abstract: 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.
authors.affiliation: 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
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.forename: Josefa
authors.initials: J
authors.lastname: Pete
authors.forename: David M
authors.initials: DM
authors.lastname: Long
authors.forename: Anna
authors.initials: A
authors.lastname: Gasser
authors.forename: David C K
authors.initials: DC
authors.lastname: Tong
authors.forename: Maryann
authors.initials: M
authors.lastname: Arnstein
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Thorpe
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017257:Ramipril / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012084:Renin-Angiotensin System; D013482:Superoxide Dismutase / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000652:urine
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C048496:N(6)-carboxymethyllysine; C406794:alagebrium; D013482:Superoxide Dismutase; D011493:Protein Kinase C; D008239:Lysine; D017257:Ramipril