Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway

2017 ◽  
Vol 474 (16) ◽  
pp. 2733-2747 ◽  
Author(s):  
Chunyang Du ◽  
Tao Zhang ◽  
Xia Xiao ◽  
Yonghong Shi ◽  
Huijun Duan ◽  
...  
Keyword(s):  
Ureteral Obstruction ◽  
Transforming Growth Factor ◽  
Unilateral Ureteral Obstruction ◽  
Mtor Pathway ◽  
Signalling Pathway ◽  
Specific Class ◽  
Protease Activated Receptor 2 ◽  
Epithelial Inflammation ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-β1 (TGF-β1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.

scholarly journals Alpha1-ACT Functions as a Tumour Suppressor in Hepatocellular Carcinoma by Inhibiting the PI3K/AKT/mTOR Signalling Pathway via Activation of PTEN

2017 ◽  
Vol 41 (6) ◽  
pp. 2289-2306 ◽  
Author(s):  
Hanzhang Zhu ◽  
Qiaoyu Liu ◽  
Junwei Tang ◽  
Yu Xie ◽  
Xiaoliang Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumour Size ◽  
Clinicopathological Characteristics ◽  
Mtor Pathway ◽  
Signalling Pathway ◽  
Migration And Invasion ◽  
The Relationship ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Background & Aims: To investigate the expression and prognostic value of α1-ACT (Alpha1-antichymotrypsin) in patients with HCC (hepatocellular carcinoma) and identify the mechanism by which α1-ACT inhibits proliferation and promotes apoptosis of HCC. Methods: We first measured α1-ACT expression levels and determined their relationship with the clinicopathological characteristics and prognosis of patients with HCC.We then established stable HCC cell lines with both α1-ACT overexpression and knockdown and performed a functional analysis in vitro.We first examined the relationship between α1-ACT and the PTEN/PI3K/AKT/mTOR pathway using Western blotting. Then, we determined whether α1-ACT can directly bind to PTEN using co-immunoprecipitation. Finally, we measured α1-ACT expression to evaluate its correlation with the PI3K/AKT/mTOR pathway-related apoptosis proteins in a xenograft tumour mouse model using immunohistochemistry. Results: The α1-ACT expression level was significantly lower in the HCC tissues than in the paratumour tissues and was negatively positively correlated with the level of Ki67, AFP, the AJCC stage, tumour size and tumour invasion. The overexpression of α1-ACT can inhibit cell proliferation and increase cell apoptosis by activating PI3K/AKT/mTOR-mediated apoptosis via binding to PTEN and activating it in vitro. Additionally, the overexpression of α1-ACT can also increase the proportion of cells in the G0/G1 stage by increasing cyclin p21 expression and inhibiting the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9. The xenotransplantation studies with nude mice also showed that overexpression of α1-ACT inhibited tumourigenesis and knockdown of α1-ACT had the opposite effect. Conclusions: Our study demonstrates that α1-ACT suppresses liver cancer development and metastasis via targeting the PTEN/PI3K/AKT/mTOR signalling pathway, which may be a potential target for therapeutic intervention in HCC.

scholarly journals 1,25-(OH)2D3 ameliorates renal interstitial fibrosis in UUO rats through the AMPKα/mTOR pathway

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098136
Author(s):  
Shasha Tian ◽  
Xiaopeng Yang ◽  
Jianwu Wang ◽  
Jing Luo ◽  
Hui Guo
Keyword(s):  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Kidney Tissue ◽  
Signalling Pathway ◽  
Sham Operation ◽  
Tubular Atrophy ◽  
Sham Operation Group ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Objective To investigate the effects of 1,25(OH)2D3 on renal fibrosis associated with the AMP-activated protein kinase (AMPK)α/mechanistic target of rapamycin (mTOR) signalling pathway in a rat model of unilateral ureteral obstruction (UUO). Methods A total of 54 male Sprague Dawley rats were randomly divided into three groups: sham-operation group, UUO group, and UUO plus calcitriol (3 ng/100 g) group. Renal tissue was excised for histological examination by immunohistochemistry and Western blot, and for gene expression analysis using real-time polymerase chain reaction. Results 1,25(OH)2D3 enhanced AMPKα levels, inhibited mTOR levels and slowed the development of interstitial fibrosis in kidney tissue. Compared with the UUO plus calcitriol group, UUO rats demonstrated more severe renal damage characterized by marked tubular atrophy, interstitial fibrosis and significant induction of fibrogenic transforming growth factor-β1 and increased extra-cellular matrix proteins (α-smooth muscle actin and collagen type III), and decreased E-cadherin. Conclusion Treatment with 1,25(OH)2D3 altered the AMPKα/mTOR signalling pathway to suppress excessive fibroblast activation observed in UUO rats. This may serve as a novel mechanism to ameliorate renal dysfunction and fibrotic lesions.

scholarly journals Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Kit San Yeung ◽  
Winnie Wan Yee Tso ◽  
Janice Jing Kun Ip ◽  
Christopher Chun Yu Mak ◽  
Gordon Ka Chun Leung ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Signalling Pathway ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals Hnf1α is required for proper gut epithelial endocrine cell specification and controls the mTOR signalling pathway in mice

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Francois Boudreau ◽  
Carine R Lussier ◽  
Francois Brial ◽  
Nathalie Rivard ◽  
Nathalie Perreault
Keyword(s):  
Endocrine Cell ◽  
Signalling Pathway ◽  
Cell Specification ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals Bone Morphogenetic Protein-2 Antagonizes Renal Interstitial Fibrosis by Promoting Catabolism of Type I Transforming Growth Factor-β Receptors

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 727-740 ◽  
Author(s):  
Yu-Lin Yang ◽  
Yi-Shiuan Liu ◽  
Lea-Yea Chuang ◽  
Jinn-Yuh Guh ◽  
Tao-Chen Lee ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ureteral Obstruction ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Morphogenetic Protein ◽  
Tgf Β1

TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-β1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-β1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-β receptors (TGF-β RI). Moreover, BMP-2 significantly shortened the half-life of TGF-β RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-β RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-β RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-β. We demonstrated that BMP-2 significantly reversed the TGF-β1-induced increase in pSmad2/3 and reversed the TGF-β1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-β RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson’s trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-β RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-β RI and Smads. Bone morphogenetic protein-2 can antagonize TGF-β-inducing cellular fibrosis by intervening post-receptors signaling, thus disclosing an application of therapeutical potential against fibrosis disorders.

scholarly journals Role of the mTOR Signalling Pathway in Human Sepsis-Induced Myocardial Dysfunction

2019 ◽  
Vol 35 (7) ◽  
pp. 875-883 ◽  
Author(s):  
Wei Cheng MM ◽  
Yun Long ◽  
Hao Wang ◽  
Wen Han MM ◽  
Jiahui Zhang ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Signalling Pathway ◽  
Human Sepsis ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

2019 ◽  
Vol 52 (3) ◽  
pp. e12571 ◽  
Author(s):  
Rui Zhao ◽  
Yinghan Song ◽  
Yong Wang ◽  
Yuqian Huang ◽  
Zhigui Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Signalling Pathway ◽  
Gastrointestinal Stromal Tumours ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

scholarly journals LncRNA MEG3 inhibits rheumatoid arthritis through miR‐141 and inactivation of AKT/mTOR signalling pathway

2019 ◽  
Vol 23 (10) ◽  
pp. 7116-7120 ◽  
Author(s):  
Guoqing Li ◽  
Ying Liu ◽  
Fanru Meng ◽  
Zhongbin Xia ◽  
Xia Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Signalling Pathway ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway
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