The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFβ1 responses in human proximal-tubule epithelial cells
TLDR
Different roles for Smad2 and Smad3 are demonstrated in TGFbeta1-induced CTGF expression and markers of EMT in human PTECs, which can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis.Abstract:
In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFβ1-Smad (transforming growth factor-β1–Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial–mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFβ are critical Smad-dependent events in the development of tubulo-interstitial fibrosis. In the present study we have investigated the distinct contributions of Smad2 and Smad3 to expression of CTGF, E-cadherin, α-SMA (α-smooth-muscle actin) and MMP-2 (matrix-metalloproteinase-2) in response to TGFβ1 treatment in an in vitro culture model of HKC-8 (transformed human PTECs). RNA interference was used to achieve selective and specific knockdown of Smad2 and Smad3. Cellular E-cadherin, α-SMA as well as secreted CTGF and MMP-2 were assessed by Western immunoblotting. TGFβ1 treatment induced a fibrotic phenotype with increased expression of CTGF, MMP-2 and α-SMA, and decreased expression of E-cadherin. TGFβ1-induced increases in CTGF and decreases in E-cadherin expression were Smad3-dependent, whereas increases in MMP-2 expression were Smad2-dependent. Increases in α-SMA expression were dependent on both Smad2 and Smad3 and were abolished by combined knockdown of both Smad2 and Smad3. In conclusion, we have demonstrated distinct roles for Smad2 and Smad3 in TGFβ1-induced CTGF expression and markers of EMT in human PTECs. This can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis.read more
Citations
More filters
Journal ArticleDOI
TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease
Brigham C. Willis,Zea Borok +1 more
TL;DR: It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
Journal ArticleDOI
New Insights into Epithelial-Mesenchymal Transition in Kidney Fibrosis
TL;DR: This review highlights the current understanding of EMT and its underlying mechanisms to stimulate further discussion on its role, not only in the pathogenesis of renal interstitial fibrosis but also in the onset of podocyte dysfunction, proteinuria, and glomerulosclerosis.
Journal ArticleDOI
TGF-β/Smad signaling in renal fibrosis
TL;DR: Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.
Journal ArticleDOI
TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis.
TL;DR: The role and molecular mechanisms of TGF-β/SMAD in the pathogenesis of hepatic fibrosis are discussed, and the possibility of novel therapeutic approaches to liver fibrotic disease is addressed by targeting to TGF -β/ SMAD signaling.
Journal ArticleDOI
Oxidative stress and glutathione in TGF-β-mediated fibrogenesis
Rui-Ming Liu,K.A. Gaston Pravia +1 more
TL;DR: This review summarizes recent findings in the field to address the potential mechanism whereby oxidative stress mediates fibrogenesis induced by TGF-beta and the potential therapeutic value of antioxidant treatment in fibrotic diseases.
References
More filters
Journal ArticleDOI
New insights into TGF-beta-Smad signalling.
Peter ten Dijke,Caroline S. Hill +1 more
TL;DR: New insights are provided into the specificity determinants of TGF-β–Smad signalling, including combinatorial ligand–receptor associations, selective interactions between the Smads and other pathway components that are mediated through defined binding motifs, and the differential regulation of duration and intensity of signalling.
Journal ArticleDOI
Epithelial to Mesenchymal Transition in Renal Fibrogenesis: Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention
TL;DR: A comprehensive review of recent advances on understanding the pathologic significance, molecular mechanism, and therapeutic intervention of EMT in the setting of chronic renal fibrosis is provided.
Journal ArticleDOI
Tubulointerstitial changes as a major determinant in the progression of renal damage.
TL;DR: This report concludes with a review of interstitial fibrosis, a pathologic process regarded as an irreversible outcome from tubulointerstitial injury.
Journal ArticleDOI
Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction
TL;DR: It is shown that mice lacking Smad3 (Smad3ex8/ex8), a key signaling intermediate downstream of the TGF-beta receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation.
Journal ArticleDOI
Connective tissue growth factor : a mediator of tgf-beta action on fibroblasts
TL;DR: Because the biological actions of TGF-β are complex and affect many different cell types, CTGF may serve as a more specific target for selective intervention in processes involving connective tissue formation during wound repair or fibrotic disorders.
Related Papers (5)
Dissection of Key Events in Tubular Epithelial to Myofibroblast Transition and Its Implications in Renal Interstitial Fibrosis
Junwei Yang,Youhua Liu +1 more
Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
Rik Derynck,Ying E. Zhang +1 more