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

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.

• Authors: Sakurako Nakamura, Tetsuya Tachikawa, Kazuki Tobita, Isao Aoyama, Fumio Takayama, Atsushi Enomoto, Toshimitsu Niwa
• Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation (Am J Kidney Dis) Vol. 41 Issue 3 Suppl 1 Pg. S68-71 (Mar 2003) ISSN: 1523-6838 [Electronic] United States
• PMID: 12612956 (Publication Type: Journal Article)

Chemical References

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

Topics

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