The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes

FASEB J. 2003 Sep;17(12):1762-4. doi: 10.1096/fj.02-1102fje. Epub 2003 Jul 18.


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

  • Albuminuria / drug therapy
  • Animal Population Groups
  • Animals
  • Blood Pressure
  • Collagen / chemistry
  • Collagen / metabolism
  • Connective Tissue Growth Factor
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Fibrosis
  • Glycation End Products, Advanced / blood
  • Glycation End Products, Advanced / metabolism*
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Kidney / chemistry
  • Kidney / pathology*
  • Kinetics
  • Lysine / analogs & derivatives*
  • Lysine / analysis
  • Lysine / immunology
  • Models, Biological
  • Rats
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / analysis
  • Receptors, Immunologic / immunology
  • Solubility
  • Thiazoles / therapeutic use*
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1
  • Tyrosine / analogs & derivatives*
  • Tyrosine / analysis


  • 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