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      Connective Tissue Growth Factor-Mediated Angiotensin II-Induced Hypertrophy of Proximal Tubular Cells

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          Background: Cellular hypertrophy is an early, important pathological feature of renal diseases such as diabetic nephropathy and remnant kidney. Recent studies have demonstrated that angiotensin II (AngII) plays a key role in mediating cell hypertrophy. The aim of our work was to explore the role of connective tissue growth factor (CTGF) in mediating AngII-induced tubular cell hypertrophy in vivoandin vitro. Methods: In an in vivo study, male Sprague-Dawley rats were randomly divided into three groups: control rats, diabetic rats and diabetic rats treated with irbesartan (IRB). The index of kidney hypertrophy (kidney weight/body weight, KW/BW), glomerular tuft area (A<sub>G</sub>), glomerular tuft volume (V<sub>G</sub>) and proximal tubular area (A<sub>T</sub>) were determined. Renal expression for CTGF was detected by immunohistochemical staining. In an in vitro study, the influence of CTGF antisense oligonucleotide (CTGF AS) on AngII-induced CTGF expression and cell hypertrophy was also investigated. Results:In an in vivo study, diabetic rats showed a significant increase of KW/BW, A<sub>G</sub>, V<sub>G</sub>, and A<sub>T</sub> from week 1 onwards compared to normal control, which could be significantly inhibited by using IRB. Furthermore, there was a significantly increasing expression of CTGF in both glomeruli and tubuli in diabetic rats compared to control, and the extent of CTGF expression closely correlated with the severity of renal hypertrophy. Treatment with IRB could markedly inhibit the renal expression of CTGF. In an in vitro study, AngII stimulated the expression of CTGF mRNA and CTGF protein. AngII significantly increased the total protein content in HK2 cells, which was markedly inhibited by co-treatment with CTGF AS. The average cellular diameter determined by scanning electronic microscope showed that the increase of cell size induced by AngII could be significantly inhibited by CTGF AS. Furthermore, flow cytometer study showed that AngII arrested the cell cycle in the G0-G1 phase, which was significantly reversed by treatment with CTGF AS. Conclusion: Our data provide both in vivo and in vitroevidence that CTGF is involved in mediating AngII-induced renal hypertrophy.

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          Most cited references 22

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          Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10

          Human umbilical vein endothelial (HUVE) cells have been previously reported to express the genes for the A and B chains of PDGF and to secrete PDGF-related factors into culture media. Antihuman PDGF IgG affinity chromatography was used to purify PDGF-related activity from HUVE cell-conditioned media. Immunoblot analysis of the affinity- purified proteins with anti-PDGF IgG and antibodies specific for the A or B chain peptides of PDGF combined with chemotactic and mitogenic assays revealed that the major PDGF immunorelated molecule secreted by HUVE cells is a monomer of approximately 36-38 kD and that less than 10% of the purified biologically active molecules are PDGF A or B chain peptides. Screening of an HUVE cell cDNA library in the expression vector lambda gtl 1 with the anti-PDGF antibody resulted in the cloning and sequencing of a cDNA with an open reading frame encoding a 38-kD cysteine-rich secreted protein which we show to be the major PDGF- related mitogen secreted by human vascular endothelial cells. The protein has a 45% overall homology to the translation product of the v- src-induced CEF-10 mRNA from chick embryo fibroblasts. We have termed this new mitogen connective tissue growth factor.
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            Angiotensin II and renal fibrosis.

            Angiotensin (Ang) II, the main peptide of the renin angiotensin system (RAS), is a renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. This vasoactive peptide activates mesangial and tubular cells and interstitial fibroblasts, increasing the expression and synthesis of extracellular matrix proteins. Some of these effects seem to be mediated by the release of other growth factors, such as TGF-beta. In experimental models of kidney damage, renal RAS activation, cell proliferation, and upregulation of growth factors and matrix production were described. In some of these models, blockade of Ang II actions by ACE inhibitors and angiotensin type 1 (AT(1)) antagonists prevents proteinuria, gene expression upregulation, and fibrosis, as well as inflammatory cell infiltration. Interestingly, Ang II could also be involved in the fibrotic process because of its behavior as a proinflammatory cytokine, participating in various steps of the inflammatory response: Ang II (1) activates mononuclear cells and (2) increases proinflammatory mediators (cytokines, chemokines, adhesion molecules, nuclear factor kappaB). Finally, Ang II also regulates matrix degradation. These data show that drugs controlling this complex vasoactive peptide are probably one of the best ways of avoiding fibrosis in progressive renal diseases.
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              Expression of connective tissue growth factor in human renal fibrosis.

              Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions. We investigated CTGF mRNA expression in 65 human renal biopsy specimens of various renal diseases by in situ hybridization. In control human kidney CTFG mRNA was mainly expressed in visceral epithelial cells, parietal epithelial cells, and some interstitial cells. Connective tissue growth factor was strongly up-regulated in the extracapillary and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. An increase in the number of cells expressing CTGF mRNA was observed at sites of chronic tubulointerstitial damage, which correlated with the degree of damage. in the tubulointerstitial area the majority of the CTGF mRNA positive cells coexpressed alpha-smooth muscle actin, and were negative for macrophage markers. Our results indicate that CTGF may be a common growth factor involved in renal fibrosis.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2006
                21 December 2005
                : 103
                : 1
                : e16-e26
                Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
                90504 Nephron Exp Nephrol 2006;103:e16–e26
                © 2006 S. Karger AG, Basel

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                Figures: 6, Tables: 7, References: 31, Pages: 1
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