Static Pressure Regulates Connective Tissue Growth Factor Expression in Human Mesangial Cells

Results suggest that high blood pressure up-regulates CTGF expression in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis.

Abstract

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress, and static pressure are possible regulatory elements in CTGF expression. In this study, we examined the ability of static pressure to modulate CTGF gene expression in cultured human mesangial cells. Low static pressure (40–80 mm Hg) stimulated cell proliferation via a protein kinase C-dependent pathway. In contrast, high static pressure (100–180 mm Hg) induced apoptosis in human mesangial cells. This effect was reversed by treatment with CTGF antisense oligonucleotide but not with transforming growth factor β1-neutralizing antibody or protein kinase C inhibitor. High static pressure not only up-regulated the expression of CTGF, but also the expression of extracellular matrix proteins (collagen I and IV, laminin). This up-regulation of extracellular matrix proteins was also reversed by treatment with CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes, including apoptosis-associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation of a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cells by transient transfection had similar effects. Taken together, these results suggest that high blood pressure up-regulates CTGF expression in mesangial cells. High levels of CTGF in turn enhance extracellular matrix production and induce apoptosis in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis. Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress, and static pressure are possible regulatory elements in CTGF expression. In this study, we examined the ability of static pressure to modulate CTGF gene expression in cultured human mesangial cells. Low static pressure (40–80 mm Hg) stimulated cell proliferation via a protein kinase C-dependent pathway. In contrast, high static pressure (100–180 mm Hg) induced apoptosis in human mesangial cells. This effect was reversed by treatment with CTGF antisense oligonucleotide but not with transforming growth factor β1-neutralizing antibody or protein kinase C inhibitor. High static pressure not only up-regulated the expression of CTGF, but also the expression of extracellular matrix proteins (collagen I and IV, laminin). This up-regulation of extracellular matrix proteins was also reversed by treatment with CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes, including apoptosis-associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation of a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cells by transient transfection had similar effects. Taken together, these results suggest that high blood pressure up-regulates CTGF expression in mesangial cells. High levels of CTGF in turn enhance extracellular matrix production and induce apoptosis in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis. connective tissue growth factor cytomegalovirus transforming growth factor β TdT-mediated dUTP biotin nick end-labeling fibroblast growth factor vascular endothelial growth factor platelet-derived growth factor 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide chelerythrine scrambled oligonucleotide neutralizing antibody extracellular signal-regulated kinase Connective tissue growth factor (CTGF)1 (1Bradham D.M. Igarashi A. Potter R.L. Grotendorst G.R. J. Cell Biol. 1991; 114: 1285-1294Crossref PubMed Scopus (806) Google Scholar, 2Oemar B.S. Luscher T.F. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1483-1489Crossref PubMed Scopus (148) Google Scholar) represents the latest addition to the list of growth factors implicated in the pathogenesis of renal fibrosis (3Gupta S. Clarkson M.R. Duggan J. Brady H.R. Kidney Int. 2000; 58: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 4Frazier K.S. Paredes A. Dube P. Styer E. Vet. Pathol. 2000; 37: w328-w335Crossref PubMed Scopus (65) Google Scholar). CTGF mRNA has been shown to be overexpressed in the extracapillary and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA nephropathy, focal, and segmental glomerulosclerosis and diabetic nephropathy (5Ito Y. Aten J. Bende R.J. Oemar B.S. Rabelink T.J. Weening J.J. Goldschmeding R. Kidney Int. 1998; 53: 853-861Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar). In anti-Thy1 nephritis, an animal model of acute glomerulonephritis, CTGF mRNA was shown to be up-regulated in both mesangial cells and podocytes (6Goldschmeding R. Aten J. Ito Y. Blom I. Rabelink T. Weening J.J. Nephrol. Dial. Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar). CTGF mRNA up-regulation in sclerotic glomeruli and fibrotic interstitium was also found in a chronic hypertension model in rats (uninephrectomized spontaneously hypertensive rats) (6Goldschmeding R. Aten J. Ito Y. Blom I. Rabelink T. Weening J.J. Nephrol. Dial. Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar). Hence, substantial evidence both in human disease as well as in experimental models of kidney disease suggests an important role of CTGF in renal diseases. Nonetheless, we have just begun to understand the regulation of CTGF expression in renal diseases. In particular, the role of high blood pressure in regulating CTGF expression has not yet been elucidated. TGF-β is thought to be the major pathogenic factor in the development of renal fibrotic disorders. However, the development and progression of renal sclerosis is determined by complex interactions of many factors, including growth factors and direct hemodynamic action. In human skin fibroblasts, CTGF mRNA is specifically induced by TGF-β but not by platelet-derived growth factor, epidermal growth factor, or basic fibroblast growth factor (6Goldschmeding R. Aten J. Ito Y. Blom I. Rabelink T. Weening J.J. Nephrol. Dial. Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar). Recent reports also suggest a possible role for hepatic growth factor, interleukin-1β, interleukin-4, tumor necrosis factor-α, and vascular endothelial growth factor (VEGF) in regulation of CTGF (6Goldschmeding R. Aten J. Ito Y. Blom I. Rabelink T. Weening J.J. Nephrol. Dial. Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar, 7Suzuma K. Naruse K. Suzuma I. Takahara N. Ueki K. Aiello L.P. King G.L. J. Biol. Chem. 2000; 275: 40725-40731Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Thus far, TGF-β has been shown to be the strongest inducer of CTGF expression in a variety of cells derived from different organs (8Grotendorst G.R. Okochi H. Hayashi N. Cell Growth Differ. 1996; 7: 469-480PubMed Google Scholar). In fact, Grotendorst et al. (8Grotendorst G.R. Okochi H. Hayashi N. Cell Growth Differ. 1996; 7: 469-480PubMed Google Scholar) found a unique TGF-β-responsive element within the promoter sequence of the CTGF gene, where point mutation of this responsive element abolished the regulatory effect of TGF-β on CTGF gene expression. More importantly, in anti-Thy1 nephritis, TGF-β and CTGF are expressed in coordinate fashion, suggesting the important role of TGF-β in regulating CTGF expressionin vivo (3Gupta S. Clarkson M.R. Duggan J. Brady H.R. Kidney Int. 2000; 58: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 6Goldschmeding R. Aten J. Ito Y. Blom I. Rabelink T. Weening J.J. Nephrol. Dial. Transplant. 2000; 15: 296-299Crossref PubMed Scopus (74) Google Scholar). Hypertension has been shown to independently accelerate the progression of chronic renal failure in humans irrespective of the pathogenesis of the renal disease (9Fogo A.B. Kidney Int. 2000; 57: S15-S21Abstract Full Text Full Text PDF Scopus (81) Google Scholar, 10Marcantoni C. Jafar T.H. Oldrizzi L. Levey A.S. Maschio G. Kidney Int. 2000; 57: S44-S48Abstract Full Text Full Text PDF Scopus (41) Google Scholar). The potential role of local hemodynamic changes on the progression of glomerulosclerosis and renal fibrosis has also been extensively studied in animal models. In patients with hypertension and diabetic nephropathy, the autoregulation of glomerular pressure is impaired, resulting in exposure of the capillary bed to systemic blood pressure fluctuation reaching unphysiologically high levels of local pressure. In normal tissue, this peak level of pressure is absorbed by the elasticity of the mesangium in the kidney glomeruli. The increased capillary pressure causes the mesangial area, including the mesangial cells to spread and expand. At the same time, the increased pressure also compresses the cells in a tangential direction. Chronic exposure to high blood pressure eventually leads to chronic expansion and remodeling of the mesangial area with accumulation of extracellular matrix and finally glomerulosclerosis. Numerous locally produced factors, including TGF-β and PDGF have been implicated in this mechanically induced mesangial expansion and remodeling. However, it is impossible to separate the effect of stretch and tangential compressive strain by pressure, in vivo. Therefore, to study these differential effects of mechanical strain on mesangial cells, we have utilized in this study an in vitro model in which only static pressure was applied to mesangial cells in culture without stretch (11Hishikawa K. Nakaki T. Suzuki H. Saruta T. Kato R. J. Cardiovasc. Pharmacol. 1992; 200 Suppl. 12: S66-S67Crossref Scopus (11) Google Scholar, 12Hishikawa K. Nakaki T. Suzuki H. Saruta T. Kato R. Eur. J. Pharmacol. 1992; 215: 329-331Crossref PubMed Scopus (68) Google Scholar, 13Hishikawa K. Nakaki T. Marumo T. Hayashi M. Suzuki H. Kato R. Saruta T. J. Clin. Invest. 1994; 93: 1975-1980Crossref PubMed Scopus (113) Google Scholar, 14Hishikawa K. Nakaki T. Marumo T. Suzuki H. Kato R. Saruta T. Hypertension. 1995; 25: 449-452Crossref PubMed Scopus (120) Google Scholar). Cyclic stretching increases production and release of various vasoactive substances and growth factors in cultured cells, including TGF-β, which in turn up-regulates CTGF mRNA expression (15Davis M.J. Meininger G.A. Zawieja D.C. Am. J. Physiol. 1992; 263: H1292-H1299Crossref PubMed Google Scholar, 16Awolesi M.A. Sessa W.C. Sumpio B.E. J. Clin. Invest. 1995; 96: 1449-1454Crossref PubMed Scopus (281) Google Scholar, 17Sumpio B.E. Widmann M.D. Ricotta J. Awolesi M.A. Watase M. J. Cell. Physiol. 1994; 158: 133-139Crossref PubMed Scopus (85) Google Scholar, 18Hishikawa K. Luscher T.F. Circulation. 1997; 96: 3610-3616Crossref PubMed Scopus (159) Google Scholar, 19Hishikawa K. Oemar B.S. Yang Z. Luscher T.F. Circ. Res. 1997; 81: 797-803Crossref PubMed Scopus (172) Google Scholar, 20Riser B.L. Denichilo M. Cortes P. Baker C. Grondin J.M. Yee J. Narins R.G. J. Am. Soc. Nephrol. 2000; 11: 25-38Crossref PubMed Scopus (21) Google Scholar). So far, the role of static pressure in regulating CTGF expression in mesangial cells has not been elucidated. We now provide direct evidence that high static pressure up-regulates CTGF levels in CTGF-mediated apoptosis. Human renal mesangial cells were obtained from Clonetics (21Amemiya T. Sasamura H. Mifune M. Kitamura Y. Hirahashi J. Hayashi M. Saruta T. Kidney Int. 1999; 56: 2055-2063Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Cells were cultured in MsGM (Clonetics), and cells from passages 2 to 4 from three different isolates were used for experiments. All experiments were performed after 24 of in antibody was obtained from with for cell of human mesangial cells in a and with the neutralizing antibody the treatment with stimulated cell proliferation in human mesangial cells, but with the neutralizing antibody The and of the neutralizing antibody is on the from was from CTGF protein and antibody were of The was as (11Hishikawa K. Nakaki T. Suzuki H. Saruta T. Kato R. J. Cardiovasc. Pharmacol. 1992; 200 Suppl. 12: S66-S67Crossref Scopus (11) Google Scholar, 12Hishikawa K. Nakaki T. Suzuki H. Saruta T. Kato R. Eur. J. Pharmacol. 1992; 215: 329-331Crossref PubMed Scopus (68) Google Scholar, 13Hishikawa K. Nakaki T. Marumo T. Hayashi M. Suzuki H. Kato R. Saruta T. J. Clin. Invest. 1994; 93: 1975-1980Crossref PubMed Scopus (113) Google Scholar, 14Hishikawa K. Nakaki T. Marumo T. Suzuki H. Kato R. Saruta T. Hypertension. 1995; 25: 449-452Crossref PubMed Scopus (120) Google Scholar). The culture and were in the pressure and the was using The pressure was using and the was in a the was the in the was that the of the in the such as and were in with In fact, were changes in and pressure of in culture the experiments to cells were to the of stretch and high static pressure. CTGF antisense oligonucleotide the was and from as T. T. Y. T. K. T. M. J. 1998; PubMed Scopus Google Scholar). oligonucleotide a scrambled sequence was used as The were to the cell culture Cell was using an to the K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar). exposure to increased static pressure mm cells were for an 4 in the of pressure. Cells were with in the and was to and mesangial cells were with with for and in for K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar). was examined using with the of cells, cells from were dUTP biotin nick end-labeling was performed with the In Cell from to the K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar). the of cells, cells from were DNA was using the Cell to the Cell were to to and with antibody for as K. Oemar B.S. Nakaki T. T. Luscher T.F. Circulation. 1999; PubMed Scopus Google Scholar). of protein were by The were using an of the were performed using the for from the of the CTGF protein in human mesangial cells, a expression the of the CTGF gene, by the was K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar, K. Oemar B.S. Nakaki T. T. Luscher T.F. Circulation. 1999; PubMed Scopus Google Scholar). cells with were used as transfection was performed using to the was by in cells with the protein gene The transfection using of and of in human mesangial cells was to be The DNA microarray experiments were performed using DNA to the The and the of genes on DNA are on the The DNA were using and the were using the of important genes are shown in 4 and and results are in the CTGF protein the expression of genes as judged by DNA microarray In human mesangial cells with recombinant CTGF for 24 extracellular matrix genes were up-regulated to The expression of anti-apoptotic genes was to and that of was up-regulated to The and in mRNA expression was as and represents the of mRNA expression to recombinant CTGF are as was to that of of the was performed using of by was of mesangial cells to static pressure mm Hg) for increased the number of cells as with cells to pressure This was by chelerythrine a protein kinase C but not by CTGF antisense oligonucleotide scrambled oligonucleotide or antibody In contrast, exposure of human mesangial cells to high static pressure and mm Hg) cell as with cells to pressure and this effect was reversed by treatment with CTGF antisense oligonucleotide but not by scrambled protein kinase C or antibody the same the of high static in cell we performed of mesangial cell culture using As shown in exposure to high static pressure mm Hg) increased the number of cells. DNA 2 and 2 that the cell number is to the in the number of cells. This effect was by treatment with CTGF antisense oligonucleotide experiments using scrambled oligonucleotide or antibody had effect suggesting that CTGF the high static apoptosis in these cells. high pressure induced CTGF expression protein level as we performed of CTGF protein expression in human mesangial cells to or mm static pressure for As shown in exposure to high static pressure mm but not to static pressure mm increased CTGF protein expression. This effect was by treatment with CTGF antisense oligonucleotide but not by oligonucleotide or antibody with protein kinase C to also had effect not the effects of CTGF on matrix human mesangial cells were in the and of CTGF antisense oligonucleotide for 24 scrambled oligonucleotide was used as The expression of extracellular matrix mRNA was using DNA The of the DNA and was to that of or The of the genes or was in and was to for as a As with cells to pressure, exposure to mm static pressure up-regulated not only CTGF mRNA but also I and and mRNA expression in human mesangial cells 4 the mRNA expression of and was by high static pressure this mm addition of CTGF antisense oligonucleotide to the culture CTGF, I and and mRNA but that of fibroblast growth factor, growth factor, vascular endothelial growth factor, and platelet-derived growth factor 4 experiments using human mesangial cells with recombinant CTGF protein similar effects suggesting an important and direct effect of CTGF in high static extracellular matrix production in these cells. the direct effects of CTGF on cell human mesangial cells were with recombinant human CTGF for As shown in treatment of mesangial cells with recombinant CTGF protein cell with increased DNA and cells. In transient transfection of human mesangial cells with an expression the of the human CTGF gene by the promoter in CTGF and of cell as well as increases in DNA and cells of human mesangial cells with had of CTGF mRNA induced apoptosis in human mesangial cells. of CTGF in human mesangial cells the number of cells as judged by Overexpression of CTGF also increased the number of mesangial cells as judged by DNA and are as the of experiments. with cells the by which CTGF apoptosis in human mesangial cells, we performed DNA microarray experiments using DNA Cells in pressure were with recombinant CTGF for 24 and mRNA expression of 1100 genes was As the genes or were used as As shown in recombinant CTGF up-regulated mRNA expression of extracellular matrix anti-apoptotic genes, including apoptosis apoptosis and were to and genes and were up-regulated to in human mesangial cells with recombinant CTGF In the study, we provide for the evidence that high static pressure up-regulation of CTGF expression and that this up-regulated CTGF expression is in of extracellular matrix and apoptosis in human mesangial cells. This is on the exposure to high static pressure increased CTGF mRNA and protein expression in human mesangial exposure to high static pressure induced apoptosis in human mesangial cells, and this effect was reversed by treatment with CTGF antisense exposure to high static pressure as well as treatment with recombinant CTGF protein increased mRNA expression of extracellular matrix protein in human mesangial cells, and this effect was by treatment with CTGF antisense treatment with recombinant CTGF protein or transient of the CTGF gene induced apoptosis in human mesangial and treatment with recombinant CTGF protein anti-apoptotic genes. evidence suggests an important role of CTGF in the development of glomerulosclerosis in patients with diabetic nephropathy (3Gupta S. Clarkson M.R. Duggan J. Brady H.R. Kidney Int. 2000; 58: 1389-1399Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, Y. Aten J. Bende R.J. Oemar B.S. Rabelink T.J. Weening J.J. Goldschmeding R. Kidney Int. 1998; 53: 853-861Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar). the by which CTGF renal in vivo is not yet et al. T. T. Y. T. K. T. M. J. 1998; PubMed Scopus Google Scholar) that high mesangial CTGF expression and matrix production by Hypertension and are well pathogenic factors in the development of glomerulosclerosis in the study the evidence that CTGF expression in cultured mesangial cells is by static pressure. CTGF in turn increased extracellular matrix production and induced apoptosis in these cells, suggesting the important role of CTGF induced by high static pressure in mesangial mesangial matrix glomerulosclerosis. Therefore, it is that high blood pressure may also the renal via CTGF pathway similar to The in proliferation of human mesangial cells induced by exposure to static pressure mm Hg) was abolished by treatment with the protein kinase C chelerythrine K. Nakaki T. Marumo T. Suzuki H. Kato R. Saruta T. Hypertension. 1995; 25: 449-452Crossref PubMed Scopus (120) Google Scholar). results were in with the effect of protein kinase C in proliferation of mesangial cells and vascular cells K. Nakaki T. Marumo T. Hayashi M. Suzuki H. Kato R. Saruta T. J. Clin. Invest. 1994; 93: 1975-1980Crossref PubMed Scopus (113) Google Scholar, Y. Z. T. M. Suzuki N. M. 1998; PubMed Scopus Google Scholar). In contrast, results that increased CTGF expression and apoptosis in human mesangial cells to high static pressure is protein kinase to the effect of high CTGF expression in mesangial cells, which is protein kinase C-dependent M. C. S. Kato S. Brady H.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). et al. M.J. Res. 2000; 275: PubMed Scopus Google Scholar) that of protein kinase C CTGF by al. K. Naruse K. Suzuma I. Takahara N. Ueki K. Aiello L.P. King G.L. J. Biol. Chem. 2000; 275: 40725-40731Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar) that vascular endothelial growth factor (VEGF) induced up-regulation of CTGF expression in capillary cells. This effect was by of protein kinase C and were only results suggest in the regulation of CTGF by a variety of pathway in different cell CTGF has been shown to be to cells and to cells (1Bradham D.M. Igarashi A. Potter R.L. Grotendorst G.R. J. Cell Biol. 1991; 114: 1285-1294Crossref PubMed Scopus (806) Google Scholar) and to induce connective tissue cell proliferation and extracellular matrix in skin in B.S. Luscher T.F. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1483-1489Crossref PubMed Scopus (148) Google Scholar). the CTGF is also expressed high levels in cell cells in lesions in human B.S. A. J.M. N. M. J. M. Luscher T.F. Circulation. 1997; PubMed Scopus Google Scholar). In human cell expression is with CTGF expression T. T. N. K. T. K. A. T. M. H. 2000; PubMed Scopus Google Scholar). Taken together, these a of CTGF in a variety of human cells. we that transient of CTGF in human cells K. Oemar B.S. Nakaki T. T. Luscher T.F. Circulation. 1999; PubMed Scopus Google Scholar) and human cells K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar) as well as treatment of these cells with recombinant human CTGF protein induced apoptosis K. Oemar B.S. Nakaki T. Luscher T.F. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (148) Google Scholar, K. Nakaki T. T. Eur. J. Pharmacol. 2000; PubMed Scopus Google Scholar). The recombinant CTGF protein used in the study was to cell proliferation of normal kidney cells in a S. and T. However, this same CTGF has effect on or human mesangial cells, or or human vascular Thus far, the for these effects of CTGF on different cell are not In transient of CTGF by transfection with the CTGF gene to be using recombinant CTGF protein in apoptosis. et al. S. T. T. T. M. 2000; PubMed Scopus Google Scholar) found that overexpressed CTGF protein was in cells with similar and that CTGF as an factor in these cells by the cell Taken together, these and suggest for CTGF on the and the cell where CTGF is the role of CTGF in human mesangial cells, we used DNA 1100 genes, including apoptosis-associated genes to genes in human mesangial cells. As shown in recombinant CTGF protein to the 1100 genes in the DNA by extracellular matrix In contrast, anti-apoptotic genes were by to and genes were up-regulated by to in human mesangial cells with recombinant CTGF protein used in this study has also been shown to induce apoptosis in cells and human vascular cells by expression and K. Oemar B.S. Nakaki T. T. Luscher T.F. Circulation. 1999; PubMed Scopus Google Scholar, K. Nakaki T. T. Eur. J. Pharmacol. 2000; PubMed Scopus Google Scholar). genes such as apoptosis protein and are to of such as J. A. K. A. Hayashi M. N. Saruta T. Kidney Int. 2000; 57: Full Text Full Text PDF PubMed Scopus Google Scholar) was also to apoptosis in human mesangial down-regulation and effect of protein and in human mesangial cells induced by high static pressure or CTGF may and the effect of high static pressure via the pathway. et al. A. J. T. S. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) that the regulation of CTGF expression in mesangial cells was by changes in is that static pressure may also modulate and modulate CTGF expression. Mechanical such as shear stress, stretch, and static pressure induce different of the cell and different but the to be stretch increased only T.J. A. Res. 1991; PubMed Scopus Google but static pressure induced high levels of production K. Nakaki T. Marumo T. Hayashi M. Suzuki H. Kato R. Saruta T. J. Clin. Invest. 1994; 93: 1975-1980Crossref PubMed Scopus (113) Google Scholar). also increased but shear and static pressure not K. Nakaki T. Marumo T. Hayashi M. Suzuki H. Kato R. Saruta T. J. Clin. Invest. 1994; 93: 1975-1980Crossref PubMed Scopus (113) Google Scholar, J. A. R. A. Res. 1991; PubMed Scopus Google Scholar). in to mechanical may high static pressure increased high level CTGF mRNA expression and stretch only induced transient of CTGF mRNA in mesangial cells B.L. Denichilo M. Cortes P. Baker C. Grondin J.M. Yee J. Narins R.G. J. Am. Soc. Nephrol. 2000; 11: 25-38Crossref PubMed Scopus (21) Google Scholar). In high static pressure to induce CTGF expression in human mesangial cells. The by which high static pressure CTGF expression and apoptosis to be elucidated. results that hypertension extracellular matrix production and apoptosis in human mesangial cells via CTGF and may a substantial role in the development of glomerulosclerosis results also suggest that CTGF as a potential for the and treatment of mesangial and sclerotic in kidney diseases.