Connective tissue growth factor and renal diseases: some answers, more questions.

PURPOSE OF REVIEW: Connective tissue growth factor (CCN2) has recently received much attention as a possible key determinant of progressive renal fibrosis. However, the mechanism(s) by which this growth factor functions is not known. The purpose of this review is to summarize and discuss the recent findings regarding the possible mechanisms involved. RECENT FINDINGS: Emerging evidence from in-vitro studies of renal cells indicates that connective tissue growth factor is a crucial mediator for transforming growth factor-beta-induced cellular dysfunction, manifest by increased cellular hypertrophy, synthesis of extracellular matrix proteins and their deposition and assembly around the cells. Indeed, recent evidence suggests that the interrelationship between connective tissue growth factor and transforming growth factor-beta is stronger than first thought. While transforming growth factor-beta induces the expression of connective tissue growth factor, the latter plays a key role in both bioactivation of latent transforming growth factor-beta and the promotion of its Smad signalling activity. SUMMARY: Connective tissue growth factor is clearly implicated in the pathogenesis of progressive renal disease. Although there is much to learn about the production, function, and mechanism of action of connective tissue growth factor, some progress has been made in understanding the molecular basis of its relationship with transforming growth factor-beta. Elucidating the signal transduction pathways activated by connective tissue growth factor will also definitely help to clarify other actions of connective tissue growth factor which may be independent of transforming growth factor-beta. Because of the inflammatory and immunosuppressive properties of transforming growth factor-beta, connective tissue growth factor seems to be an attractive alternative therapeutic target for combating renal fibrosis.

Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy.

Connective tissue growth factor (CTGF) is now considered to be one of the important driver molecules for the pathogenesis of diabetic nephropathy (DN) and possibly many other fibrotic disorders. However, the molecular mechanisms by which CTGF functions remain to be established. In an attempt to define these mechanisms, this study was designed to investigate whether CTGF has any effect on the cell cycle of human mesangial cells (HMC), which are known to undergo hypertrophy in DN. This report provides the first evidence that CTGF is a hypertrophic factor for HMC. CTGF stimulates HMC to actively enter the G(1) phase from G(0), but they do not then progress further through the cell cycle. The molecular mechanisms underlying this G(1) phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15(INK4), p21(Cip1), and p27(Kip1), which are known to bind and inactivate cyclinD/CDK4/6 and the cyclin E/CDK2 kinase complexes. This could account for the maintenance of pRb protein in a non- or very low-phosphorylated state, preventing cell cycle progression. Using CTGF antisense oligonucleotides, the results also indicate that the previously identified transforming growth factor-beta (TGF-beta)-induced hypertrophy in mesangial cells is CTGF-dependent. Mesangial cell hypertrophy is one of the earliest abnormalities of diabetic nephropathy; therefore, therapeutic strategies targeting CTGF may be beneficial in controlling DN.

Decorin suppresses transforming growth factor-beta-induced expression of plasminogen activator inhibitor-1 in human mesangial cells through a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-240.

Transforming growth factor-beta (TGFbeta) is a key mediator of extracellular matrix (ECM) accumulation in sclerotic kidney diseases such as diabetic nephropathy. One of the main target cells for TGFbeta in the kidney are glomerular mesangial cells, which respond by increasing expression of ECM proteins, such as collagens, laminin and fibronectin, while suppressing the expression of ECM-degrading proteases and increasing the synthesis of ECM protease inhibitors, including plasminogen activator inhibitor-1. Previous studies have shown that exposure of mesangial cells to chronic high-glucose conditions, such as those seen in diabetes, increases ECM deposition in a mechanism involving glucose-mediated up-regulation of TGFbeta expression. Naturally occurring inhibitors of this TGFbeta-dependent fibrotic response include decorin, a small leucine-rich proteoglycan. While the mechanism by which TGFbeta stimulates gene expression via the Smad signal-transduction pathway is becoming clear, the precise mechanism by which decorin may impinge upon TGFbeta activity remains to be established. In this study, for the first time we provide evidence that decorin can disrupt glucose- and TGFbeta/Smad-dependent transcriptional events in human mesangial cells through a mechanism that involves an increase in Ca(2+) signalling, the activation of Ca(2+)/calmodulin-dependent protein kinase II and ensuing phosphorylation of Smad2 at Ser-240. We show that decorin also induces Ser-240 phospho-Smad hetero-oligomerization with Smad4 and the nuclear localization of this complex independently of TGFbeta receptor activation. Thus, in human mesangial cells, the mechanism of decorin-mediated inhibition of TGFbeta signalling may involve activation of Ca(2+) signalling, the subsequent phosphorylation of Smad2 at a key regulatory site, and the sequestration of Smad4 in the nucleus.