Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy

• Published in: Kidney international Vol. 60; no. 1; pp. 96 - 105
• Main Authors: Wang, Shinong, Denichilo, Mark, Brubaker, Carrie, Hirschberg, Raimund
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2001; Nature Publishing; Elsevier Limited
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; chronic renal failure; collagen; Collagen - metabolism; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; end-stage renal disease; Fibroblasts - metabolism; Fibronectins - metabolism; Fibrosis; Gene Expression Regulation; Growth Substances - genetics; Growth Substances - physiology; Hepatocyte Growth Factor - metabolism; IGF-I; Immediate-Early Proteins - genetics; Immediate-Early Proteins - physiology; Insulin-Like Growth Factor I - physiology; Intercellular Signaling Peptides and Proteins; Interstitial nephritis; Kidney - pathology; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidney Tubules - pathology; Male; Medical sciences; Mice; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; progressive interstitial nephritis; Rats; Rats, Sprague-Dawley; thrombospondin; Transforming Growth Factor beta - metabolism; thrombospondin; progressive interstitial nephritis; collagen; IGF-I; end-stage renal disease; chronic renal failure; Endocrinopathy; Kidney disease; Cell culture; Animal model; Urinary system disease; Rat; Transforming growth factor β; Diabetes mellitus; Rodentia; Terminal stage; Experimental study; In vitro; Connective tissue; Vertebrata; Chronic; Mammalia; Nephropathy; Animal; Tubulointerstitial nephritis; Renal failure; Growth factor
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.2001.00776.x

Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy. 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). The expression of CTGF was examined in rats with diabetic nephropathy. Regulation and actions of CTGF were studied in in vitro cell culture models. 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-β (TGF-β) and hepatocyte growth factor (HGF), induced increased CTGF expression in tubular cells. TGF-β1 and, to a lesser extent, HGF also raised CTGF expression in cultured proximal tubular cells. In contrast, high glucose (25mmol/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 α1III 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 α1III. CTGF is expressed and regulated downstream from TGF-β 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-β and HGF and may contribute to chronic tubulointerstitial fibrosis in diabetic nephropathy.