Interaction between the polyol pathway and non-enzymatic glycation on mesangial cell gene expression.
OBJECTIVE
Both activation of the polyol pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the interaction between these two pathways using normal mesangial cells (MCs) and transgenic (TG) MCs with elevated aldose reductase (AR) activity.


METHODS
TG mice with expression of the human AR (hAR) gene in kidney MCs were established. Mouse glomeruli and primary cultures of MCs from hAR TG and wild-type (WT) mice were studied regarding the changes in AR activity, transforming growth factor-beta1 (TGF-beta1) and type IV collagen mRNA and protein levels, in response to BSA modified by advanced glycation end-products (AGE-BSA).


RESULTS
Ex vivo addition of AGE-BSA increased AR activity, TGF-beta1 and type IV collagen mRNA levels in both WT and TG glomeruli, with greater rise in TG glomeruli. These increments were attenuated by zopolrestat, an AR inhibitor. In cultured MCs, AGE-BSA enhanced AR activity, TGF-beta(1) and type IV collagen mRNA and protein levels both in WT and TG MCs, again with greater increases in TG MCs. The AGE-induced enhancement in TGF-beta1 and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide.


CONCLUSIONS
These data suggest that the activation of the polyol pathway by AGEs, more marked in genetic conditions with increased AR activity, may contribute to the pathogenesis of diabetic glomerulopathy, through enhancing mesangial cell expression of TGF-beta1 and type IV collagen.
Dan
Qinghong
Q
Department of Medicine, The University of Hong Kong, Hong Kong, PR China.
Wong
Rachel L C
RL
Yin
Shinan
S
Chung
Sookja K
SK
Chung
Stephen S M
SS
Lam
Karen S L
KS
D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D024141:Collagen Type IV / Q000096:biosynthesis* / Q000502:physiology; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000502:physiology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000473:pathology; D007064:L-Iditol 2-Dehydrogenase; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012710:Serum Albumin, Bovine; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase