Static pressure regulates connective tissue growth factor expression in human mesangial cells

Connective tissue growth factor (CTGF) is overexpressed in a variety of fib rotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a c ommon final pathway of renal diseases of diverse etiology, including inflam mation, hemodynamics, and metabolic injury, Mechanical strains such as stre tch, shear stress,and static pressure are possible regulatory elements in C TGF expression. In this study, we examined the ability of static pressure t o modulate CTGF gene expression in cultured human mesangial cells. Low stat ic pressure (40-80 mm Hg) stimulated cell proliferation via a protein kinas e C-dependent pathway. In contrast, high static pressure (100-180 mm Hg) in duced apoptosis in human mesangial cells. This effect was reversed by treat ment with CTGF antisense oligonucleotide but not with transforming growth f actor pi-neutralizing antibody or protein kinase C inhibitor. High static p ressure not only up-regulated the expression of CTGF, but also the expressi on of extracellular matrix proteins (collagen I and TV, laminin), This up-r egulation of extracellular matrix proteins was also reversed by treatment w ith CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes, including apoptoisis-associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation o f a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cel ls by transient transfection had similar effects. Taken together, these res ults suggest that high blood pressure up-regulates CTG;F expression in mesa ngial cells. High levels of CTGF in turn enhance extracellular matrix produ ction and induce apoptosis in mesangial cells, and may contribute to remode ling of mesangium and ultimately glomerulosclerosis.