The MSP‐RON pathway regulates liver fibrosis through transforming growth factor beta‐dependent epithelial–mesenchymal transition

Weng, Tian-Hao; Dong, Yan; Shi, Danrong; Zhu, Miaojin; Liu, Yizhi; Wu, Zhigang; Tang, Tian; Zhu, Linwei; Zhang, Hong; Yao, Hang‐Ping; Li, Lanjuan

doi:10.1111/liv.14892

Cited by 6 publications

(4 citation statements)

References 46 publications

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“…Many fibrosis processes are often accompanied by enhanced transduction of the TGF-β signaling pathway. 34 , 35 Similarly, the TGF-β/SMAD signaling pathway has always been the focus of research on capsule formation and contracture. 36 Activation of this pathway can stimulate fibroblasts to synthesize collagen and promote fibroblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Progranulin Promotes the Formation and Development of Capsules Caused by Silicone in Sprague-Dawley Rats

Zhou¹,

Pang²,

Wang³

et al. 2022

CCID

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Background Silicone implants are currently the most widely used artificial materials in plastic surgery. Capsule formation following implant application is unavoidable. When the capsule is excessively thick and strongly contracted, it can lead to obvious symptoms, clinically known as capsular contracture. Biological factors have always been the focus of research on the capsule formation. As a growth factor, progranulin (PGRN) plays an important regulatory role in wound healing, tissue fibrosis, tumor proliferation and invasion, and inflammation regulation. At present, the research on the capsule mainly involves the regulation of tissue healing and fibrosis under the influence of inflammation. Because PGRN has a regulatory role in these processes, we believe that the study of both can provide a new theoretical basis and intervention sites for monitoring and inhibiting the development of the capsule. Methods In this experiment, the effects of different surgical operations on the content of PGRN in the surgical site and plasma of rats were detected. Sprague-Dawley (SD) rat dermal fibroblasts were co-cultured by recombinant PGRN. The effects of r-PGRN on fibroblasts were detected by 5-ethynyl-2’-deoxyuridine (EdU) assay, wound healing assay and Western blot assay. Finally, the effect of PGRN on capsule formation and contracture was studied by changing the content of PGRN in the prosthesis in rats after operation. Results Surgical trauma and silicone implant increased plasma and local PGRN levels in SD rats. PGRN can activate the TGF-β/SMAD signaling pathway in a dose-dependent manner, thereby promoting fibroblast proliferation, differentiation and migration and inhibiting apoptosis and enhancing cell function, thereby promoting capsule formation and contracture. Conclusion PGRN promotes the formation and contracture of the silicone implant capsule in SD rats by activating the TGF-β/SMAD signaling pathway. This discovery may provide new therapeutic targets and detection indicators.

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Section: Discussionmentioning

confidence: 99%

Progranulin Promotes the Formation and Development of Capsules Caused by Silicone in Sprague-Dawley Rats

Zhou¹,

Pang²,

Wang³

et al. 2022

CCID

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“…Inhibiting TGFβ signaling restores the ECM, regulates tumor vasculature, reverses epithelial-mesenchymal transition (EMT), damages cancer stem cells, and can enhance the response to chemotherapy ( 30 , 31 ). Activation of the TGFβ signaling pathway promotes hepatocyte EMT and fibrosis progression in animal models ( 32 ). In vitro , EMT is induced by TGFβ in bile duct epithelial cells, causing BA fibrosis ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Reduced peroxisome proliferator-activated receptor-α and bile acid nuclear receptor NR1H4/FXR may affect the hepatic immune microenvironment of biliary atresia

Tan

et al. 2022

Front. Immunol.

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BackgroundBiliary atresia (BA) is a childhood liver disease characterized by fibrous obstruction and obstruction of the extrahepatic biliary system and is one of the most common and serious biliary disorders in infants. Significant inflammation and fibrosis of the liver and biliary tract are the most prominent features, regardless of the initial damage to the BA. Abnormalities in innate or adaptive immunity have been found in human patients and mouse models of BA. We previously reported that children with BA had abnormal lipid metabolism, including free serum carnitine.ObjectiveTo study gene and protein expression levels of the hepatic peroxisome proliferator-activated receptor-α (PPARα) signaling pathway and farnesoid X receptor (FXR) in BA and BA fibrosis, and assess their clinical values.MethodsLow expression of PPARα and NR1H4 (FXR) in BA were validated in the Gene Expression Omnibus database. Functional differences were determined by gene set enrichment analysis based on of PPARα and NR1H4 expression. BA patients from GSE46960 were divided into two clusters by using consensus clustering according to PPARα, NR1H4, and SMAD3 expression levels, and immunoinfiltration analysis was performed. Finally, 58 cases treated in our hospital were used for experimental verification. (IHC: 10 Biliary atresia, 10 choledochal cysts; PCR: 10 Biliary atresia, 14 choledochal cysts; WB: 10 Biliary atresia, 4 choledochal cysts).ResultsBioinformatics analysis showed that the expression of PPARα, CYP7A1 and NR1H4 (FXR) in the biliary atresia group was significantly lower than in the control group. More BA-specific pathways, including TGFβ signaling pathway, P53 signaling pathway, PI3K-AKT-mTOR signaling pathway, etc., are enriched in BA patients with low PPARα and NR1H4 expression. In addition, low NR1H4 expression is abundant in inflammatory responses, IL6/STAT3 signaling pathways, early estrogen responses, IL2 STAT5 signaling pathways, and TGFβ signaling pathways. The TGFβ signaling pathway was significant in both groups. According to the expression of PPARα, NR1H4 and SMAD3, a key node in TGFβ pathway, BA patients were divided into two clusters using consensus clustering. In cluster 2, SMAD3 expression was high, and PPARα and NR1H4 expression were low. In contrast to cluster 1, immune cell infiltration was higher in cluster 2, which was confirmed by immunohistochemistry. The mRNA and protein levels of PPARα and NR1H4 in BA patients were lower than in the control group by immunohistochemistry, Western blot analysis and real-time PCR.ConclusionsThe downregulation of PPARα and NR1H4 (FXR) signaling pathway may be closely related to biliary atresia.

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“…e increased expression of TGF-β1 and α-SMA is a manifestation of epithelial-to-mesenchymal transition (EMT). In the formation of renal interstitial fibrosis (RIF), EMT is believed to play an important role in organ fibrosis [4], chronic inflammation [5], tissue reconstruction [6], and various fibrotic diseases [7].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Rhein on Renal Interstitial Fibrosis via the SHH-Gli1 Signal Pathway

Luo

Jiang

Cheng

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Rhein is the main extract of Rheum palmatum L., which has been proved to improve the renal function of chronic kidney disease, but its mechanism is not clear. Therefore, this experiment explored the potential pharmacological effect of rhein on renal interstitial fibrosis rats. Methods. This study explores the potential pharmacological action of rhein. In this work, we investigate the potential pharmacological action of rhein in unilateral urethral obstruction (UUO) rats. Thirty Sprague Dawley rats were randomly divided into three groups: sham, UUO, and rhein (rhein-treated UUO rats) groups. The left ureters of the UUO group rats were exposed and bluntly dissected. The rhein group rats were administered an intragastric gavage of rhein (2 mg·kg−1·d−1) for 14 d. Kidney function-related indicators were monitored in these rats, while indexes of pathologic aspects were determined histologically. The expression of α-SMA, TGF-β1, SHH, Gli1, and Snail was quantified using real-time polymerase chain reaction and western blotting. The NRK-49F cells were incubated with and without SHH (100 ng·ml−1) for 48 hours. The SHH-activated NRK-49F cells were incubated with cyclopamine (CNP, 20 umol L−1) or rhein (1 ng·ml−1). The Gli1 and Snail mRNA and protein level were detected. Results. In the in vivo experiment, the results exhibited that UUO caused renal pathological damages. However, these changes could be significantly reversed by the administration of rhein. Compared with the untreated UUO group, the rhein group showed reduced kidney tubular atrophy and necrosis, interstitial fibrosis, hyperplasia, and abnormal deposition of extracellular matrix. Rhein reduced the RNA and protein expression of SHH, Gli1, and Snail of the UUO rats. In the in vitro experiment, CNP or rhein treatment decreased the expression of Gli1 and Snail on mRNA and protein levels in SHH-induced NRK-49F cells, suggesting that CNP or rhein suppresses SHH-induced NRK-49F activation. Taken together, these results demonstrated that rhein suppresses SHH-Gli1-Snail signal pathway activation, with potential implications for the treatment of renal fibrosis. Conclusions. Treatment with rhein remarkably ameliorated renal interstitial fibrosis in UUO rats by regulating the SHH-Gli1-Snail signal pathway.

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The MSP‐RON pathway regulates liver fibrosis through transforming growth factor beta‐dependent epithelial–mesenchymal transition

Cited by 6 publications

References 46 publications

Progranulin Promotes the Formation and Development of Capsules Caused by Silicone in Sprague-Dawley Rats

Progranulin Promotes the Formation and Development of Capsules Caused by Silicone in Sprague-Dawley Rats

Reduced peroxisome proliferator-activated receptor-α and bile acid nuclear receptor NR1H4/FXR may affect the hepatic immune microenvironment of biliary atresia

Inhibitory Effects of Rhein on Renal Interstitial Fibrosis via the SHH-Gli1 Signal Pathway

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