Renal connective tissue growth factor induction in experimental diabetes is prevented by aminoguanidine.
The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF.
Twigg
Stephen M
SM
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Cao
Zemin
Z
MCLennan
Sue V
SV
Burns
Wendy C
WC
Brammar
Gail
G
Forbes
Josephine M
JM
Cooper
Mark E
ME
D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000517:prevention & control; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000494:pharmacology
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D006146:Guanidines; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; D012710:Serum Albumin, Bovine; C048496:N(6)-carboxymethyllysine; D008239:Lysine; C004479:pimagedine