Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy.
BACKGROUND
Chronic interstitial fibrosis, which follows the onset of glomerular proteinuria, importantly contributes to progressive renal failure in diabetic nephropathy. The present studies examine the potential role of tubular connective tissue growth factor (CTGF).


METHODS
The expression of CTGF was examined in rats with diabetic nephropathy. Regulation and actions of CTGF were studied in in vitro cell culture models.


RESULTS
CTGF mRNA levels were increased in the renal cortex of rats with streptozotocin-induced diabetes compared with controls. Immunohistology indicated that CTGF was expressed in renal cortex of diabetic rats, in contrast to controls in some tubular cross-sections, particularly dilated-appearing proximal tubules, in which it tended to colocalize with insulin-like growth factor-I (IGF-I). Glomerular ultrafiltrate from diabetic rats, which contained bioactive transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF), induced increased CTGF expression in tubular cells. TGF-beta1 and, to a lesser extent, HGF also raised CTGF expression in cultured proximal tubular cells. In contrast, high glucose (25 mmol/L) did not increase the secretion of CTGF. In cultured tubular cells, rhCTGF moderately increased fibronectin but not collagen (Col) type I and type III expression. In NRK-49F renal interstitial fibroblasts, CTGF raised Col alpha1III and thrombospondin-1 levels. CTGF has an IGF-binding domain and binds to IGF-I. In NRK-49F cells, IGF-I increased the activity of CTGF towards the expression of Col alpha1III.


CONCLUSIONS
CTGF is expressed and regulated downstream from TGF-beta and HGF in proximal tubular cells, is induced by diabetic rat glomerular ultrafiltrate, and has moderate profibrogenic activity in tubular cells and renal interstitial fibroblasts, where its activity is IGF-I dependent. By these means, CTGF may act downstream of TGF-beta and HGF and may contribute to chronic tubulointerstitial fibrosis in diabetic nephropathy.
Wang
S
S
Division of Nephrology and Hypertension, Harbor-UCLA Research and Education Institute, Torrance, and Fibrogen Inc., South San Francisco, California, USA.
Denichilo
M
M
Brubaker
C
C
Hirschberg
R
R
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D005353:Fibronectins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D003094:Collagen