Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose.

Tubulointerstitial fibrosis is an important component in the development of diabetic nephropathy. Various renal cell types, including fibroblasts, contribute to the excessive matrix deposition in the kidney. Although transforming growth factor-beta (TGF-beta) has been thought to play a major role during fibrosis, other growth factors are also involved. Here we examined the effects of connective tissue growth factor (CTGF) and IGF-I on collagen type I and III production by human renal fibroblasts and their involvement in glucose-induced matrix accumulation. We have demonstrated that both CTGF and IGF-I expressions were increased in renal fibroblasts under hyperglycemic conditions, also in the absence of TGF-beta signaling. Although CTGF alone had no effect on collagen secretion, combined stimulation with IGF-I enhanced collagen accumulation. Furthermore, IGF-I also had a synergistic effect with glucose on the induction of collagens. Moreover, we observed a partial inhibition in glucose-induced collagen secretion with neutralizing anti-CTGF antibodies, thereby demonstrating for the first time the involvement of endogenous CTGF in glucose-induced effects in human renal fibroblasts. Therefore, the cooperation between CTGF and IGF-I might be involved in glucose-induced matrix accumulation in tubulointerstitial fibrosis and might contribute to the pathogenesis of diabetic nephropathy.

[1]  A. Flyvbjerg,et al.  Kidney tissue somatomedin C and initial renal growth in diabetic and uninephrectomised rats , 1988, Diabetologia.

[2]  居軒 功.  Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis , 2004 .

[3]  M. Daha,et al.  Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-beta1. , 2003, Kidney international.

[4]  Peter Vorwerk,et al.  Binding properties of insulin-like growth factor binding protein-3 (IGFBP-3), IGFBP-3 N- and C-terminal fragments, and structurally related proteins mac25 and connective tissue growth factor measured using a biosensor. , 2002, Endocrinology.

[5]  V. Hwa,et al.  Connective tissue growth factor/IGF-binding protein-related protein-2 is a mediator in the induction of fibronectin by advanced glycosylation end-products in human dermal fibroblasts. , 2002, Endocrinology.

[6]  E. D. De Robertis,et al.  Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. , 2002, Nature cell biology.

[7]  B. Brenner,et al.  Pathogenesis of diabetic nephropathy: focus on transforming growth factor-β and connective tissue growth factor , 2001, Current opinion in nephrology and hypertension.

[8]  B. Weston,et al.  Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. , 2001, The Biochemical journal.

[9]  M. DeNichilo,et al.  Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy. , 2001, Kidney international.

[10]  T. Rabelink,et al.  In vitro evidence for differential involvement of CTGF, TGFbeta, and PDGF-BB in mesangial response to injury. , 2001, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[11]  A. Joly,et al.  Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus. , 2001, Endocrinology.

[12]  A. Flyvbjerg.  Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease , 2000, Diabetologia.

[13]  J. Rossert,et al.  Growth factors, cytokines, and renal fibrosis during the course of diabetic nephropathy. , 2000, Diabetes & metabolism.

[14]  R. Baxter.  Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. , 2000, American journal of physiology. Endocrinology and metabolism.

[15]  L. Thal,et al.  Blood Levels of Alpha-1-Antichymotrypsin and Risk Factors for Alzheimer’s Disease: Effects of Gender and Apolipoprotein E Genotype , 2000, Dementia and Geriatric Cognitive Disorders.

[16]  J. Yee,et al.  Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis. , 2000, Journal of the American Society of Nephrology : JASN.

[17]  V. Hwa,et al.  The Insulin-like Growth Factor-binding Protein (igfbp) Superfamily* , 2022 .

[18]  M. Takigawa,et al.  Role and interaction of connective tissue growth factor with transforming growth factor‐β in persistent fibrosis: A mouse fibrosis model , 1999, Journal of cellular physiology.

[19]  Gary R. Grotendorst,et al.  Connective tissue growth factor mediates transforming growth factor b-induced collagen synthesis : down-regulation by cAMP , 1999 .

[20]  D. C. Han,et al.  High glucose stimulates proliferation and collagen type I synthesis in renal cortical fibroblasts: mediation by autocrine activation of TGF-beta. , 1999, Journal of the American Society of Nephrology : JASN.

[21]  C. Pollock,et al.  Cyclosporin exerts a direct fibrogenic effect on human tubulointerstitial cells: roles of insulin-like growth factor I, transforming growth factor beta1, and platelet-derived growth factor. , 1999, The Journal of pharmacology and experimental therapeutics.

[22]  F. Martin,et al.  Suppression Subtractive Hybridization Identifies High Glucose Levels as a Stimulus for Expression of Connective Tissue Growth Factor and Other Genes in Human Mesangial Cells* , 1999, The Journal of Biological Chemistry.

[23]  D. Clemmons.  Role of insulin-like growth factor binding proteins in controlling IGF actions , 1998, Molecular and Cellular Endocrinology.

[24]  R. Bende,et al.  Expression of connective tissue growth factor in human renal fibrosis. , 1998, Kidney international.

[25]  R. Baxter,et al.  Human renal fibroblasts modulate proximal tubule cell growth and transport via the IGF-I axis. , 1997, Kidney international.

[26]  E. Wilson,et al.  Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Phillip,et al.  Renal hypertrophy in hyperglycemic non-obese diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I. , 1997, Journal of the American Society of Nephrology : JASN.

[28]  T. Hostetter,et al.  Diabetic nephropathy. , 1997, Journal of the American Society of Nephrology : JASN.

[29]  Gary R. Grotendorst,et al.  Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. , 1996, The Journal of investigative dermatology.

[30]  G. Romeo,et al.  Insulin-like growth factors I and II stimulate extracellular matrix production in human glomerular mesangial cells. Comparison with transforming growth factor-beta. , 1996, Endocrinology.

[31]  R. Westendorp,et al.  Progression of chronic renal disease in humans is associated with the deposition of basement membrane components and decorin in the interstitial extracellular matrix. , 1995, Clinical nephrology.

[32]  K. Sharma,et al.  Hyperglycemia and Diabetic Kidney Disease: The Case for Transforming Growth Factor–β as a Key Mediator , 1995, Diabetes.

[33]  S. Adler,et al.  Insulin-like growth factor I induces mesangial proliferation and increases mRNA and secretion of collagen. , 1995, Kidney international.

[34]  Schreiber Bd,et al.  Insulin-like growth factor-1 stimulates production of mesangial cell matrix components. , 1995 .

[35]  A. Eddy,et al.  Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. , 1995, Kidney international.

[36]  H. Rodemann,et al.  Human renal fibroblast cell lines (tFKIF and tNKF) are new tools to investigate pathophysiologic mechanisms of renal interstitial fibrosis. , 1995, Experimental nephrology.

[37]  A. E. El Nahas,et al.  Insulin-like growth factor-I and experimental diabetic kidney disease. , 1993, Experimental nephrology.

[38]  M. Steffes,et al.  An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. , 1992, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[39]  R. Bilous,et al.  Cell and Matrix Components of the Glomerular Mesangium in Type I Diabetes , 1992, Diabetes.

[40]  E. Schleicher,et al.  Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. , 1991, The American journal of pathology.

[41]  I. Figari,et al.  The autocrine production of transforming growth factor-beta 1 during lymphocyte activation. A study with a monoclonal antibody-based ELISA. , 1990, Journal of immunology.

[42]  G. Jerums,et al.  Effect of Puberty on Initial Kidney Growth and Rise in Kidney IGF-I in Diabetic Rats , 1990, Diabetes.

[43]  A. Reddi,et al.  Diabetic nephropathy. An update. , 1990, Archives of internal medicine.