Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.
Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A(1c) and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.
Yamamoto
Y
Y
Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. yamamoto@med.kanazawa-u.ac.jp
Kato
I
I
Doi
T
T
Yonekura
H
H
Ohashi
S
S
Takeuchi
M
M
Watanabe
T
T
Yamagishi
S
S
Sakurai
S
S
Takasawa
S
S
Okamoto
H
H
Yamamoto
H
H
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013830:Thiadiazoles / Q000494:pharmacology*; D053778:Thiazolidines
D017127:Glycation End Products, Advanced; C105739:OPB 9195; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013830:Thiadiazoles; D053778:Thiazolidines