Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195.
OBJECTIVE
Advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy. We reported earlier that OPB-9195, a synthetic thiazolidine derivative and novel inhibitor of advanced glycation, prevented progression of diabetic glomerulosclerosis by lowering serum concentrations of advanced glycation end products and reducing their deposition in the glomeruli. Here, we examined their contribution and that of growth factors, such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF), to the progression of diabetic nephropathy. We also investigated the expression of type IV collagen in the kidneys of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model, after treatment with OPB-9195.


METHODS
Using northern blots and immunohistochemical techniques, we determined the renal expression of TGF-beta and type IV collagen mRNAs and proteins in OLETF rats. We also examined OPB-9195's effects on renal expression of VEGF mRNA and protein.


RESULTS
Concomitant increases in TGF-beta and type IV collagen expression were observed at each point in time in OLETF rats not given OPB-9195. In contrast, OPB-9195 treatment greatly suppressed the renal expression of TGF-beta, VEGF and type IV collagen mRNAs and proteins to that seen in non-diabetic rats.


CONCLUSIONS
Since OPB-9195, an AGE-inhibitor, prevented the progression of diabetic nephropathy by blocking type IV collagen production and suppressing overproduction of two growth factors, TGF-beta and VEGF, in diabetic rats, this compound warrants further investigation.
Tsuchida
K
K
Department of Medicine II, Hokkaido University School of Medicine, Sapporo, Japan.
Makita
Z
Z
Yamagishi
S
S
Atsumi
T
T
Miyoshi
H
H
Obara
S
S
Ishida
M
M
Ishikawa
S
S
Yasumura
K
K
Koike
T
T
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003094:Collagen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000737:chemistry; D008222:Lymphokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D013830:Thiadiazoles / Q000627:therapeutic use*; D053778:Thiazolidines; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001786:Blood Glucose; D016228:Endothelial Growth Factors; D017127:Glycation End Products, Advanced; D008222:Lymphokines; C105739:OPB 9195; D012333:RNA, Messenger; D013830:Thiadiazoles; D053778:Thiazolidines; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003094:Collagen