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.
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Renal mitochondrial oxidative damage occurs in 32-week streptozotocin diabetic rats, manifest as lucigenin luminescence in kidney slices.
“Coughlan et al. (72) demonstrated renal mitochondrial oxidative damage in 32-week streptozotocin diabetic rats manifest as lucigenin luminescence in kidney slices, an effect that was reduced by alagebrium, a crosslink inhibitor of advanced glycosylation end product (AGE) accumulation.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [72]
Alagebrium reduced renal mitochondrial oxidative damage in 32-week streptozotocin diabetic rats.
“Coughlan et al. (72) demonstrated renal mitochondrial oxidative damage in 32-week streptozotocin diabetic rats manifest as lucigenin luminescence in kidney slices, an effect that was reduced by alagebrium, a crosslink inhibitor of advanced glycosylation end product (AGE) accumulation.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [72]
Renal carboxymethyl lysine, an AGE marker of glycoxidation and lipid peroxidation, was inhibited by alagebrium, linking oxidative damage to protein glycosylation.
“Interestingly, renal carboxymethyl lysine, an AGE marker of glycoxidation and lipid peroxidation, also was inhibited, linking oxidative damage to protein glycosylation.”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [72]
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Self-citation
- Authors
- Coughlan, M. T., Thallas-Bonke, V., Pete, J., Long, D. M., Gasser, A., Tong, D. C. K., Arnstein, M., Thorpe, S. R., Cooper, M. E., & Forbes, J. M.
- Affiliations
- Juvenile Diabetes Research Foundation (AU)
- University of South Carolina (US)
- Monash University (AU)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-02
- Volume
- 148
- Issue
- 2
- Pages
- 886-895
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W1968299608
- Cited by
- 124
- References
- 51
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 5 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 9 · 2013: 12 · 2012: 6
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (NIDDK-19971)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- alagebrium, advanced glycation end products, ACE inhibitors, ramipril, diabetic nephropathy, combination therapy, albuminuria, carboxymethyllysine, soluble receptor for advanced glycation end products, renin-angiotensin system, oxidative stress, mitochondrial oxidative stress, protein kinase C, nuclear factor-kappaB, vascular endothelial growth factor, renal protection
- MeSH terms
- Receptor for Advanced Glycation End Products, Angiotensin-Converting Enzyme Inhibitors, Animals, Cytosol, Diabetes Mellitus, Experimental, Drug Synergism, Drug Therapy, Combination, Enzyme Activation, Kidney, Lysine, Male, Mitochondria, Protein Kinase C, Receptors, Immunologic, Renin-Angiotensin System, Superoxide Dismutase, Thiazoles, NF-kappa B, Glycation End Products, Advanced, Rats, Sprague-Dawley, Ramipril, Oxidative Stress, Vascular Endothelial Growth Factor A, Rats
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