Modulation of the cytoskeletal architecture was shown to regulate the expression of CTGF (connective tissue growth factor, CCN2). The microtubule disrupting agents nocodazole and colchicine strongly up-regulated CTGF expression, which was prevented upon stabilization of the microtubules by paclitaxel. As a consequence of microtubule disruption, RhoA was activated and the actin stress fibers were stabilized. Both effects were related to CTGF induction. Overexpression of constitutively active RhoA induced CTGF synthesis. Interference with RhoA signaling by simvastatin, toxinB, C3 toxin, and Y27632 prevented up-regulation of CTGF. Likewise, direct disintegration of the actin cytoskeleton by latrunculin B interfered with nocodazolemediated up-regulation of CTGF expression. Disassembly of actin fibers by cytochalasin D, however, unexpectedly increased CTGF expression indicating that the content of F-actin per se was not the major determinant for CTGF gene expression. Given the fact that cytochalasin D sequesters G-actin, a decrease in G-actin increased CTGF, while increased levels of Gactin corresponded to reduced CTGF expression. These data link alterations in the microtubule and actin cytoskeleton to the expression of CTGF and provide a molecular basis for the observation that CTGF is up-regulated in cells exposed to mechanical stress.

Objective-Angiotensin II is recognized as one of the major mediators of cardiovascular pathology. Because connective tissue growth factor (CTGF) is involved in the pathophysiologic processes underlying fibrotic diseases, its regulation by angiotensin II was investigated. Methods and Results-In the 2-kidney, 1-clip model of renovascular hypertension, increased expression of CTGF was detectable in the hypertrophic left ventricle. ngiotensin II is the primary effector molecule of the renin-angiotensin system, and as such, it plays a central role in the regulation of arterial blood pressure and the etiology of hypertension. Apart from its pressure effects, angiotensin II exerts a variety of nonhemodynamic effects that are linked to cardiovascular and renal pathology. 1 By binding to and activation of angiotensin II type 1 (AT 1 ) receptors, angiotensin II mediates renal or cardiac fibrosis. 2 The fibrogenic effects of angiotensin II are often related to the cytokine transforming growth factor-␤ (TGF-␤). In vivo and in vitro data show the high capacity of TGF-␤ to induce the synthesis of extracellular matrix proteins and to prevent their degradation, thus leading to excess deposition of extracellular matrix and fibrosis (summarized in Eddy 3 ). It was shown in various cellular systems and animal studies that interference with TGF-␤ signaling reduced angiotensin II-mediated synthesis of matrix molecules (reviewed in Kim and Iwao 1 and Williams 4 ).Connective tissue growth factor (CTGF) is a member of the CYR61, CTGF, and NOV protein family, structurally characterized by their cysteine-rich sequence. 5 Functionally, CTGF was characterized as a downstream mediator of TGF-␤, mediating many but not all of the profibrotic actions of this cytokine. 6 TGF-␤ was shown to be the strongest inducer of CTGF in most cells, but other factors such as bioactive lipids have also been implicated in CTGF induction. 7,8 In injury-induced animal models of cardiac hypertrophy, increased levels of CTGF were observed. 9,10 In cyclosporin A-induced myocardial lesions, CTGF was reduced when the renin-angiotensin II system was blocked. 11 CTGF was similarly reduced in diabetic nephropathy when the animals were treated with an angiotensin II receptor blocker, 12 suggesting a link between angiotensin II and CTGF expression. These animal models, however, did not allow elucidation of the molecular mechanisms of this relation.Angiotensin II exerts its diverse biologic effects by binding to 2 types of receptors, AT 1 and AT 2 , both of which belong to the group of heptahelical transmembrane receptors. Depending on the cell type and stimulus, coupling to various different intracellular pathways mediates the physiologic and pathophysiologic actions of angiotensin II (summarized in Touyz and Schiffrin 13 ). Given the profibrotic effects of angiotensin II, we hypothesized that

Statins were identified as potent inhibitors of ccn2 (ctgf) mRNA expression in mesangial cells, and therefore might be of potential use to modulate the excessive ccn2 (ctgf) expression in mesangial cells related to glomerular fibrosis.