Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Sato, Misako; Muragaki, Yasuteru; Saika, Shizuya; Roberts, Anita B.; Ooshima, Akira

doi:10.1172/jci19270

Cited by 523 publications

(595 citation statements)

References 48 publications

(25 reference statements)

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“…For example, TGF-β1 mRNA auto-induction is thought to have a beneficial role in cardiac wound healing after ischemic injury [44] , whilst auto-induction of TGF-β1 at the site of injury in the proximal tubule may result in a positive feedback, where sustained cytokine production may accelerate EMT and increase the generation of myofibroblasts thus promoting and exacerbating fibrosis. A correlation between Smads and AP-1 has also been suggested following elegant studies performed in a mouse model of unilateral ureteric obstruction and in fibroblasts obtained from Smad2 and Smad3 knockout animals [45][46]. These studies confirmed not only a correlation between Smad signalling and TGF-β1 auto-induction, but further demonstrated that the relationship depended on the presence and activation of Smad3.…”

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confidence: 64%

“…The majority of TGFs regulated in EMT rely on Smad3-dependent transcriptional regulation [45]. Recent studies in renal proximal tubule cells demonstrated angiotensin II-induced tubular EMT was Smad3-dependent [48], whilst (β)1-integrin gene expression, a potential 8 therapeutic target of renal fibrosis is also up-regulated in both unilateral obstruction and in chronic tubulointerstitial fibrosis via a Smad3-dependent mechanism [49].…”

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confidence: 99%

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The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

172

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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confidence: 64%

mentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

172

187

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“…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). TGF-␤1 induces cell hypertrophy in the early phase of fibrotic disease and may promote epithelial cell-to-mesenchyme transition and apoptosis in later stages of fibrotic diseases (9).…”

Section: Discussionmentioning

confidence: 85%

“…Our data indicate that KCP can suppress the TGF-␤ response in renal epithelial cells and help maintain the epithelial phenotype. In animal models of renal disease, TGF-␤ is a profibrotic cytokine that is thought to mediate the transition of epithelial cells to mesenchyme (15,23). Previously, we showed that KCP null mice were hypersensitive to developing renal fibrosis by either the ATN model or the UUO model (11).…”

Section: Resultsmentioning

confidence: 99%

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

Lin¹,

Patel

Wang³

et al. 2006

Molecular and Cellular Biology

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The transforming growth factor ␤ (TGF-␤) superfamily, including the bone morphogenetic protein (BMP) and TGF-␤/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-␤ but inhibited by BMP7. In this report, the effects of KCP on TGF-␤/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A-and TGF-␤1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-␤1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-␤ and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-␤ activation indicates a critical role for KCP in modulating the responses between these antiand profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.The transforming growth factor ␤ (TGF-␤) superfamily encodes growth and differentiation factors that regulate a wide variety of cellular processes. The members of the TGF-␤ superfamily include two major branches, bone morphogenetic proteins (BMPs) and TGF-␤s/activins (19). TGF-␤ signaling is initiated by the binding of the ligand to a specific pair of type I and type II transmembrane receptors, leading to the phosphorylation of the cytoplasmic serine/threonine kinase domains (19,25). The type I receptors, also known as activinlinked kinases (ALKs), then transduce signals downstream by phosphorylation of receptor-activated Smad proteins. The Smad family can be divided into three distinct subfamilies: receptor-activated Smads (R-Smad), common-partner Smads (Co-Smad), and inhibitory Smads. Whereas Smad1, Smad5, and Smad8 are phosphorylated by BMP type I receptors (ALK-2, ALK-3, and ALK-6), Smad2 and Smad3 are activated by TGF-␤ and activin type I receptors (ALK-5 and ALK-4). The R-Smad and the Co-Smad (Smad4) form a heterooligomer which translocates into the nucleus and regulates expression of ligand-responsive genes. Inhibitory Smads include Smad6 and Smad7, which prevent the activation of R-and Co-Smad.While members of the TGF-␤ superfamily use similar mechanisms to signal to the nucleus, the two major branches achieve specificity by using different elements. Outside the cell, each ligand of the TGF-␤ superfamily binds to specific pairs of the recept...

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“…Several studies in different cell types have already aimed at distinguishing between the specific roles of Smad2 and Smad3, which share biochemical properties, in TGFβ signaling. The majority of these data were obtained from the assessment of transcriptional responses in Smad2 and Smad3 knockout cells, including fibroblasts, hepatocytes, as well as epithelial cells from lens and renal tubules (19)(20)(21)(22)(23)(24). Both of these latter types of epithelial cell also undergo EMT in response to TGFβ, which has been proposed to contribute to fibrosis in the kidney or in the lens after injury.…”

Section: Discussionmentioning

confidence: 99%

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

Dzwonek

Preobrazhenska

Cazzola

et al. 2009

Molecular Cancer Research

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Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed, including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases, and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342-53)

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Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction

Abstract: MethodsUUO. Smad3-null (Smad3 ex8/ex8 ) mice were generated as described (13) and were used at 6-8 weeks of age and 20-30 g in body weight. In mice sedated by general anes-

Cited by 523 publications

References 48 publications

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

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

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

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