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 beta1-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.
Highlights
Connective tissue growth factor (CTGF)1 [1, 2] represents the latest addition to the list of growth factors implicated in the
Exposure of human mesangial cells to high static pressure (140 and 180 mm Hg) significantly reduced cell viability as compared with cells exposed to atmospheric pressure (Fig. 1A), and this effect was reversed by treatment with CTGF antisense oligonucleotide but not by scrambled oligonucleotide, protein kinase C inhibitor, or TGF-1-neutralizing antibody at the same concentrations (Fig. 1C)
We provide for the first time evidence that high static pressure induces up-regulation of CTGF expression and that this up-regulated CTGF expression is involved in overproduction of extracellular matrix and apoptosis in human mesangial cells
Summary
Connective tissue growth factor (CTGF)1 [1, 2] represents the latest addition to the list of growth factors implicated in the. CTGF mRNA up-regulation in sclerotic glomeruli and fibrotic interstitium was found in a chronic hypertension model in rats (uninephrectomized spontaneously hypertensive rats) [6]. Substantial evidence both in human disease as well as in experimental models of kidney disease suggests an important role of CTGF in renal diseases. 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.
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