scholarly journals Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication

2008 ◽  
Vol 294 (5) ◽  
pp. F1076-F1083 ◽  
Author(s):  
Ruoyun Tan ◽  
Weichun He ◽  
Xia Lin ◽  
Lawrence P. Kiss ◽  
Youhua Liu
Keyword(s):  
Epithelial Cells ◽  
Ectopic Expression ◽  
Fine Tuning ◽  
Type I ◽  
Renal Tubules ◽  
Target Specificity ◽  
Tubular Epithelial Cells ◽  
Regulatory Factor ◽  
Functional Implication ◽  
Tgf Β1

Smad ubiquitination regulatory factor-2 (Smurf2) is an E3 ubiqutin ligase that plays a pivotal role in regulating TGF-β signaling via selectively targeting key components of the Smad pathway for degradation. In this study, we have investigated the regulation of Smurf2 expression, its target specificity, and the functional implication of its induction in the fibrotic kidney. Immunohistochemical staining revealed that Smurf2 was upregulated specifically in renal tubules of kidney biopsies from patients with various nephropathies. In vitro, Smurf2 mRNA and protein were induced in human proximal tubular epithelial cells (HKC-8) upon TGF-β1 stimulation. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad2, but not Smad1, Smad3, Smad4, and Smad7, in HKC-8 cells. Interestingly, Smurf2 was also able to downregulate the Smad transcriptional corepressors Ski, SnoN, and TG-interacting factor. Inhibition of the proteasomal pathway prevented Smurf2-mediated downregulation of Smad2 and Smad corepressors. Functionally, overexpression of Smurf2 enhanced the transcription of the TGF-β-responsive promoter and augmented TGF-β1-mediated E-cadherin suppression, as well as fibronectin and type I collagen induction in HKC-8 cells. These results indicate that Smurf2 specifically targets both positive and negative Smad regulators for destruction in tubular epithelial cells, thereby providing a complex fine-tuning of TGF-β signaling. It appears that dysregulation of Smurf2 could contribute to an aberrant TGF-β/Smad signaling in the pathogenesis of kidney fibrosis.

scholarly journals Identification of a microRNA signature in renal fibrosis: role of miR-21

2011 ◽  
Vol 301 (4) ◽  
pp. F793-F801 ◽  
Author(s):  
Abolfazl Zarjou ◽  
Shanzhong Yang ◽  
Edward Abraham ◽  
Anupam Agarwal ◽  
Gang Liu
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Response To Treatment ◽  
Tubular Epithelial Cells ◽  
Altered Expression ◽  
Tnf Α ◽  
Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

scholarly journals Autocrine Transforming Growth Factor-β1 Activation Mediated by Integrin αVβ3 Regulates Transcriptional Expression of Laminin-332 in Madin-Darby Canine Kidney Epithelial Cells

2010 ◽  
Vol 21 (21) ◽  
pp. 3654-3668 ◽  
Author(s):  
Jose V. Moyano ◽  
Patricia G. Greciano ◽  
Mary M. Buschmann ◽  
Manuel Koch ◽  
Karl S. Matlin
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Integrin Αvβ3 ◽  
Type I ◽  
Madin Darby Canine Kidney ◽  
Epithelial Regeneration ◽  
Tgf Β1 ◽  
Darby Canine Kidney ◽  
Canine Kidney

Laminin (LM)-332 is an extracellular matrix protein that plays a structural role in normal tissues and is also important in facilitating recovery of epithelia from injury. We have shown that expression of LM-332 is up-regulated during renal epithelial regeneration after ischemic injury, but the molecular signals that control expression are unknown. Here, we demonstrate that in Madin-Darby canine kidney (MDCK) epithelial cells LM-332 expression occurs only in subconfluent cultures and is turned-off after a polarized epithelium has formed. Addition of active transforming growth factor (TGF)-β1 to confluent MDCK monolayers is sufficient to induce transcription of the LM α3 gene and LM-332 protein expression via the TGF-β type I receptor (TβR-I) and the Smad2–Smad4 complex. Significantly, we show that expression of LM-332 in MDCK cells is an autocrine response to endogenous TGF-β1 secretion and activation mediated by integrin αVβ3 because neutralizing antibodies block LM-332 production in subconfluent cells. In confluent cells, latent TGF-β1 is secreted apically, whereas TβR-I and integrin αVβ3 are localized basolaterally. Disruption of the epithelial barrier by mechanical injury activates TGF-β1, leading to LM-332 expression. Together, our data suggest a novel mechanism for triggering the production of LM-332 after epithelial injury.

Formin mDia1 contributes to migration and epithelial‐mesenchymal transition of tubular epithelial cells exposed to TGF‐β1

2019 ◽  
Vol 121 (8-9) ◽  
pp. 3861-3870 ◽  
Author(s):  
Yu‐Ying Li ◽  
Guo‐Tao Jiang ◽  
Li‐Jie Chen ◽  
Yan‐Hong Jiang ◽  
Jun‐Dong Jiao
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Tgf Β1

scholarly journals Lefty A protein inhibits TGF-β1-mediated apoptosis in human renal tubular epithelial cells

2013 ◽  
Vol 8 (2) ◽  
pp. 621-625 ◽  
Author(s):  
REN-PING ZHENG ◽  
TAO BAI ◽  
XIAO-GUANG ZHOU ◽  
CHANG-GEN XU ◽  
WEI WANG ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Tgf Β1

scholarly journals Distinctive role of Stat3 and Erk-1/2 activation in mediating interferon-γ inhibition of TGF-β1 action

2006 ◽  
Vol 290 (5) ◽  
pp. F1234-F1240 ◽  
Author(s):  
Myrto Giannopoulou ◽  
Steven C. Iszkula ◽  
Chunsun Dai ◽  
Xiaoyue Tan ◽  
Junwei Yang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Ectopic Expression ◽  
Interferon Γ ◽  
Signal Pathways ◽  
Tubular Epithelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Ifn Γ ◽  
Pai 1

Interferon-γ (IFN-γ) is a multifunctional cytokine that elicits antifibrotic activity in a variety of organs. In this study, we investigated the potential role and mechanism of IFN-γ in modulating the fibrogenic action of transforming growth factor (TGF)-β1 in tubular epithelial cells. Incubation of human proximal tubular epithelial (HKC) cells with IFN-γ inhibited TGF-β1-mediated α-smooth muscle actin (α-SMA) expression. IFN-γ also abolished TGF-β1-induced fibronectin and plasminogen activator inhibitor-1 (PAI-1) expression. To explore the mechanisms by which INF-γ inhibits TGF-β1 action, the signaling pathways that are critical for mediating the antifibrotic activity of IFN-γ were studied. Stimulation of HKC cells with IFN-γ triggered a sustained activation of Erk-1/2 and signal transducer and activator of transcription-3 (Stat3). Blockade of Erk-1/2 activation with an Mek1 inhibitor abolished the inhibitory effect of IFN-γ on α-SMA expression, whereas inhibition of Stat3 activation had no influence. Constitutive activation of Erk-1/2 by ectopic expression of activated Mek1 mimicked IFN-γ and suppressed TGF-β1-mediated α-SMA expression. Interestingly, inhibition of Stat3 activation abolished the ability of IFN-γ to attenuate TGF-β1-mediated PAI-1 and fibronectin expression in HKC cells. These findings indicate that IFN-γ is capable of antagonizing the fibrogenic actions of TGF-β1 in renal tubular epithelial cells. The antifibrotic action of IFN-γ appears to be mediated through a coordinated activation of both Erk-1/2 and Stat3 signal pathways in a mutually independent fashion.

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