TGF-β signal transduction and mesangial cell fibrogenesis

Abstract

Transforming growth factor-β (TGF-β) is closely associated with progressive renal fibrosis. Significant progress has been accomplished in determining the cellular signaling pathways that are activated by TGF-β. This knowledge is being applied to glomerular mesangial cell models of extracellular matrix (ECM) accumulation. A central component of TGF-β-stimulated mesangial cell fibrogenesis is the TGF-β family-specific Smad signal transduction pathway. However, while Smads play an important role in collagen accumulation, recent findings indicate that cross talk among a variety of pathways is necessary for maximal stimulation of collagen expression. Further investigation of these multiple interactions will provide insight into possible ways to interrupt cellular mechanisms of glomerular fibrogenesis.

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Elevated expression of TGF-␤ 1 is a major stimulant for ECM accumulation by mesangial cells through regulation of genes encoding ECM, PAI-1, and other proteins through Smads and extracellular signal-regulated kinase (ERK) (13,17,18,19,29,36,44,57,68,69,71). In this study, we found for the first time that two initial effects of high ambient glucose, the generation of ROS by NADPH oxidase and activation of PKC-are dependent on signal transduction initiated by TGF-␤ 1 .…”

“…The most potent of these, TGF-␤ 1 , contributes to glomerular ECM accumulation by increasing the expression of ECM genes, such as collagen I and IV, and fibronectin and by decreasing ECM degradation through elevated expression of plasminogen activator inhibitor-1 (PAI-1) and other effects on mesangial cells (17,34,44). TGF-␤ 1 expression and activation play a pathogenic role in mesangial expansion in diabetic nephropathy (68,69).…”

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

“…Renal fibrosis is due to an increase in interstitial fibroblasts and increased deposition of basement membrane components. Currently, TGF-␤1 is regarded as the predominant profibrotic stimulus in the kidney and many other tissues (3,17,22). Consistent with this hypothesis, deletion of the downstream effector Smad3 protects against fibrotic disease in the kidney after obstruction (15).…”

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

“…We and others have established that Smads are key transducers of TGF-␤-stimulated mesangial cell fibrogenesis and play a critical role in kidney fibrosis (17,42). In the diabetic milieu, Smad activation was demonstrated by increased nuclear phospho-Smad2 staining in glomerular cells in db/db mice (43) or by increased glomerular nuclear Smad binding element binding associated with fibronectin promoter activation in STZ diabetic C57Bl mice (44).…”