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


CONCLUSIONS
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.
Nakamura
Sakurako
S
Department of Clinical Preventive Medicine, Nagoya University Hospital, Nagoya, Japan.
Tachikawa
Tetsuya
T
Tobita
Kazuki
K
Aoyama
Isao
I
Takayama
Fumio
F
Enomoto
Atsushi
A
Niwa
Toshimitsu
T
D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect / Q000379:methods; D005920:Glomerular Mesangium / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D020334:Rats, Inbred OLETF; D011919:Rats, Inbred Strains; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D053778:Thiazolidines
D000911:Antibodies, Monoclonal; D017127:Glycation End Products, Advanced; C105739:OPB 9195; D013830:Thiadiazoles; D053778:Thiazolidines; C048496:N(6)-carboxymethyllysine; D008239:Lysine