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/kg⅐d; wk 0 -32); alagebrium (10 mg/kg⅐d; 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-B 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. (Endocrinology 148: 886 -895, 2007)

Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models

“…ApoA-I and ApoB levels in human plasma were measured using a COBAS Integra 400 Plus blood analyser. AGE levels in human plasma and isolated HDL were measured as carboxymethyl lysine (CML) using an assay from MBL International (Woburn, MA, USA) and AGE levels in mouse plasma were measured as described previously [23]. The amounts of labelled cholesterol and cholesteryl esters in mouse plasma were established after separating aliquots of mouse plasma using thin layer chromatography as described previously [24].…”

Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

“…2, 8). In experimental diabetic nephropathy, alagebrium chloride decreases renal mitochondrial ROS generation, which is not seen with RAS blockade (38). Indeed, the utility of alagebrium chloride is currently being investigated in type 1 diabetic patients with microalbuminuria treated with concomitant ACE inhibition (PHASE IIb, http://www.…”

“…Indeed, angiotensin II itself can produce ROS primarily via NADPH oxidase (42), and it is likely that strategies that interrupt the RAS significantly decrease ROS generation. However, one cannot exclude that RAS blockade may not fully suppress ROS generation, particularly from other sources such as mitochondria (38), and indeed this could explain the persistent progression, albeit at a slower rate, seen in subjects with diabetic nephropathy concomitantly treated with agents that interrupt the RAS. Therefore, it is worth considering as an important strategy identification of new therapeutic targets that could lead to new treatments that confer synergistic effects with those seen with RAS blockade.…”

Influence of pyridoxylidene aminoguanidine on biomarkers of the oxidative stress and selected metabolic parameters of rats with diabetes mellitus

“…The compounds are searched for, which could prevent the formation AGEs or eliminate their effect (Vasan et al 2003;Thomas et al 2005;Machado et al 2006;Coughlan et al 2007;Tanimoto et al 2007;Muellenbach et al 2008). One of these compounds is aminoguanidine (AG), which was, thanks to its effect, proposed for the prevention of diabetic complications (Giardino et al 1998;Gül et al 2008;Wu et al 2008).…”