Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells

Liu, Xiujuan; Hong, Quan; Wang, Zhen; Yu, Yanyan; Zou, Xin; Xu, Li‐Hong

doi:10.1177/1535370215605586

Cited by 37 publications

(25 citation statements)

References 31 publications

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“…Several studies have demonstrated that miR-21 level is elevated in lung tissues from PAH patients and mice PAH models [29], and miR-21 up-regulation contributes to pulmonary vascular remodeling via promoting PASMC proliferation in the pathogenesis of PAH [30,31]. Liu et al have found that SphK1/S1P pathway increases miR-21 expression to promote fibrosis in renal tubular epithelial cells [32]. Degagné et al have further demonstrated that signal transducer and activator of transcription 3 (STAT3) medicates S1P-induced upregulation of miR-21 in colonic epithelial cells [33].…”

Section: Discussionmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. Methods: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. Results: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. Conclusion: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

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Section: Discussionmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

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“…Consistent with this, two of the most upregulated miRNAs observed in patients with active EoE, miR-21 and miR-223, have been shown to have functions that would support a pathologic role in EoE. miR-21 is implicated in eosinophil survival, allergic inflammation, and TGF-β-stimulated tissue fibrosis [61–63]. Similarly, miR-223 has been implicated in regulating IL-5 expression and eosinophil development [64].…”

Section: Genetics Epigenetics and Transcriptional Analysesmentioning

confidence: 88%

The Immunologic Mechanisms of Eosinophilic Esophagitis

Hill

Spergel

2016

Curr Allergy Asthma Rep

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Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease that is triggered by food and/or environmental allergens and is characterized by a clinical and pathologic phenotype of progressive esophageal dysfunction due to tissue inflammation and fibrosis. EoE is suspected in patients with painful swallowing, among other symptoms, and is diagnosed by the presence of 15 or more eosinophils per high-power field in one or more of at least four esophageal biopsy specimens. The prevalence of EoE is increasing and has now reached rates similar to those of other chronic gastrointestinal disorders such as Crohn’s disease. In recent years, our understanding of the immunologic mechanisms underlying this condition has grown considerably. Thanks to new genetic, molecular, cellular, animal, and translational studies, we can now postulate a detailed pathway by which exposure to allergens results in a complex and coordinated type 2 inflammatory cascade that, if not intervened upon, can result in pain on swallowing, esophageal strictures, and food impaction. Here, we review the most recent research in this field to synthesize and summarize our current understanding of this complex and important disease.

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“…Inflammation is an important contributor to cholestasis‐induced liver injury . S1P and S1PRs have been identified as key players in various fibrotic diseases, including LF . Recent studies reported that S1PR2/3‐mediated homing of bone‐marrow–derived immune cells contributes to cholestasis‐induced liver fibrosis .…”

Section: Discussionmentioning

confidence: 99%

The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

et al. 2017

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Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the AKT and ERK1/2 signaling pathways via the sphingosine 1-phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)-induced apoptosis. However, the role of S1PR2 in bile acid-mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA- and S1P-induced activation of ERK1/2 and AKT were inhibited by JTE-013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA- and S1P-induced cell proliferation and migration were inhibited by JTE-013 and a specific shRNA of S1PR2 as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, the expression of S1PR2 was upregulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL-induced cholangiocyte proliferation and cholestatic injury as indicated by significant reduction of inflammation and liver fibrosis in S1PR2−/− mice. Treatment of BDL mice with JTE-013 significantly reduced total bile acid levels in the serum and cholestatic liver injury. This study suggests that the CBA-induced activation of S1PR2-mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases.

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Transforming growth factor-β-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells

Cited by 37 publications

References 31 publications

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

The Immunologic Mechanisms of Eosinophilic Esophagitis

The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

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