Roles of connective tissue growth factor and prostanoids in early streptozotocin-induced diabetic rat kidney: the effect of aspirin treatment.
BACKGROUND
Connective tissue growth factor (CTGF) is a cysteine-rich growth factor induced by transforming growth factor-beta (TGF-beta) and is thought to play a critical role in TGF-beta-stimulated extracellular matrix accumulation. To explore its involvement in early diabetic nephropathy, we investigated the time course of CTGF gene expression and its regulation in streptozotocin (STZ)-induced diabetic rat kidney.


METHODS
Northern blot analysis for CTGF, TGF-beta, and fibronectin expression was performed in the glomeruli of STZ-induced diabetic rats from 3 days to 12 weeks after the induction of diabetes, together with histological examination. To investigate the role of prostanoids in this process, aspirin was administered in one group of diabetic rats. Furthermore, CTGF expression was analyzed in rat mesangial cells cultured under high-glucose conditions.


RESULTS
Glomerular expression of CTGF and TGF-beta1 mRNA was coordinately upregulated as early as day 3, followed by fibronectin induction and mesangial matrix accumulation. Chronic aspirin treatment in diabetic rats significantly attenuated mesangial expansion, and effectively suppressed CTGF induction, as well as inhibiting the upregulation of TGF-beta1 and fibronectin expression. In cultured mesangial cells, aspirin treatment abolished high glucose-stimulated CTGF upregulation.


CONCLUSIONS
These results indicate that CTGF expressed in the glomeruli is upregulated in the early stage of STZ-induced diabetic nephropathy in rats, and could be a critical mediator of the development of diabetic glomerulosclerosis. In addition, the modulatory effects of aspirin during this process suggest a role of the cyclooxygenase pathway in the progression of diabetic nephropathy.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. muko@kuhp.kyoto-u.ac.jp
Hisashi
H
Makino
Masashi
M
Mukoyama
Akira
A
Sugawara
Kiyoshi
K
Mori
Takayoshi
T
Suganami
Kensei
K
Yahata
Yuriko
Y
Fujinaga
Hideki
H
Yokoi
Issei
I
Tanaka
Kazuwa
K
Nakao
D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D015152:Blotting, Northern; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000209:etiology; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000737:chemistry / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000737:chemistry; D007700:Kinetics; D008297:Male; D011453:Prostaglandins / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
C526316:CCN2 protein, rat; D016861:Cyclooxygenase Inhibitors; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D005947:Glucose; D001241:Aspirin