An inhibitor of advanced glycation end product formation reduces N epsilon-(carboxymethyl)lysine accumulation in glomeruli of diabetic rats

Am J Kidney Dis. 2003 Mar;41(3 Suppl 1):S68-71. doi: 10.1053/ajkd.2003.50088.

Abstract

Background: An inhibitor of advanced glycation, OPB-9195, retards the progression of nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus. The aim of this study is to evaluate histologically the role of N(epsilon)-(carboxymethyl)lysine (CML) in the development of diabetic nephropathy and investigate whether inhibition of CML accumulation by OPB-9195 is associated directly with the prevention of glomerular lesions in OLETF rats.

Methods: Kidneys of OLETF and Long-Evans Tokushima Otsuka rats were obtained at ages 7, 20, 50, and 68 weeks after collecting their blood and urine samples. OPB-9195 had been administered to the rats from age 24 weeks to the end of the experiments. CML in kidneys was detected by using a monoclonal antibody against CML according to an indirect immunofluorescence technique. CML-positive glomerular area was measured using NIH Image software (Research Services Branch of NIMH, Bethesda, MD). Hyalinized and/or sclerotic areas in glomeruli and mesangial and glomerular volume were measured using a point-counting technique.

Results: CML-positive area in glomeruli correlated closely not only with urinary albumin excretion (r = 0.912; P = 0.001), but also with volumes of mesangium and hyalinized and/or sclerotic lesions (r = 0.859; P = 0.0019 and r = 0.833; P = 0.0027, respectively). Treatment with OPB-9195 reduced CML-positive area and prevented the increase in mesangial volume, with no significant change in glomerular volume at age 68 weeks. The volume of hyalinized and/or sclerotic lesions also decreased by treatment with OPB-9195 in three of four rats at age 68 weeks.

Conclusion: CML is a major advanced glycation end product contributing to the development of diabetic nephropathy, and inhibition of its accumulation by OPB-9195 results in amelioration of glomerular lesions in OLETF rats.

MeSH terms

  • Age Factors
  • Animals
  • Antibodies, Monoclonal / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control
  • Disease Models, Animal
  • Fluorescent Antibody Technique, Indirect / methods
  • Glomerular Mesangium / chemistry
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / metabolism
  • Glomerular Mesangium / physiopathology
  • Glycation End Products, Advanced / antagonists & inhibitors*
  • Glycation End Products, Advanced / metabolism*
  • Kidney / chemistry
  • Kidney / drug effects
  • Kidney / physiopathology
  • Kidney Glomerulus / chemistry
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / physiopathology
  • Lysine / analogs & derivatives*
  • Lysine / immunology
  • Lysine / metabolism*
  • Lysine / physiology
  • Rats
  • Rats, Inbred OLETF
  • Rats, Inbred Strains
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / pharmacology
  • Thiadiazoles / therapeutic use
  • Thiazolidines

Substances

  • Antibodies, Monoclonal
  • Glycation End Products, Advanced
  • OPB 9195
  • Thiadiazoles
  • Thiazolidines
  • N(6)-carboxymethyllysine
  • Lysine