Abstract |
Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
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Authors | Josephine M Forbes, Vicki Thallas, Merlin C Thomas, Hank W Founds, Wendy C Burns, George Jerums, Mark E Cooper |
Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 17
Issue 12
Pg. 1762-4
(Sep 2003)
ISSN: 1530-6860 [Electronic] United States |
PMID | 12958202
(Publication Type: Journal Article)
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Chemical References |
- CCN2 protein, rat
- Glycation End Products, Advanced
- Immediate-Early Proteins
- Intercellular Signaling Peptides and Proteins
- Receptor for Advanced Glycation End Products
- Receptors, Immunologic
- Tgfb1 protein, rat
- Thiazoles
- Transforming Growth Factor beta
- Transforming Growth Factor beta1
- Connective Tissue Growth Factor
- 3-nitrotyrosine
- Tyrosine
- N(6)-carboxymethyllysine
- Collagen
- alagebrium
- Lysine
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Topics |
- Albuminuria
(drug therapy)
- Animal Population Groups
- Animals
- Blood Pressure
- Collagen
(chemistry, metabolism)
- Connective Tissue Growth Factor
- Diabetes Mellitus, Experimental
(complications)
- Diabetic Nephropathies
(drug therapy, metabolism, pathology)
- Fibrosis
- Glycation End Products, Advanced
(blood, metabolism)
- Immediate-Early Proteins
(biosynthesis, genetics)
- Immunohistochemistry
- Intercellular Signaling Peptides and Proteins
(biosynthesis, genetics)
- Kidney
(chemistry, pathology)
- Kinetics
- Lysine
(analogs & derivatives, analysis, immunology)
- Models, Biological
- Rats
- Receptor for Advanced Glycation End Products
- Receptors, Immunologic
(analysis, immunology)
- Solubility
- Thiazoles
(therapeutic use)
- Transforming Growth Factor beta
(biosynthesis, genetics)
- Transforming Growth Factor beta1
- Tyrosine
(analogs & derivatives, analysis)
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