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.
MeSH terms
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Albuminuria / drug therapy
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Animal Population Groups
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Animals
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Blood Pressure
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Collagen / chemistry
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Collagen / metabolism
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Connective Tissue Growth Factor
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Diabetes Mellitus, Experimental / complications*
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Diabetic Nephropathies / drug therapy*
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Diabetic Nephropathies / metabolism
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Diabetic Nephropathies / pathology
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Fibrosis
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Glycation End Products, Advanced / blood
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Glycation End Products, Advanced / metabolism*
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / genetics
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Intercellular Signaling Peptides and Proteins / genetics
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Kidney / chemistry
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Kidney / pathology*
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Kinetics
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Lysine / analogs & derivatives*
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Lysine / analysis
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Lysine / immunology
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Models, Biological
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Rats
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / analysis
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Receptors, Immunologic / immunology
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Solubility
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Thiazoles / therapeutic use*
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta1
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Tyrosine / analogs & derivatives*
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Tyrosine / analysis
Substances
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CCN2 protein, rat
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Glycation End Products, Advanced
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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Tgfb1 protein, rat
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Thiazoles
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Connective Tissue Growth Factor
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3-nitrotyrosine
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Tyrosine
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N(6)-carboxymethyllysine
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Collagen
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alagebrium
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Lysine