JAK3/STAT6 Stimulates Bone Marrow–Derived Fibroblast Activation in Renal Fibrosis

Objective: Renal fibrosis is a common pathway leading to the progression of chronic kidney disease. Activated fibroblasts contribute remarkably to the development of renal fibrosis. Although apigenin has been demonstrated to play a protective role from fibrotic diseases, its pharmacological effect on renal fibroblast activation remains largely unknown. Materials and Methods: Here, we examined the functional role of apigenin in the activation of renal fibroblasts response to transforming growth factor (TGF)-β1 and its potential mechanisms. Cultured renal fibroblasts (NRK-49F) were exposed to apigenin (1, 5, 10 and 20 μM), followed by the stimulation of TGF-β1 (2 ng/mL) for 24 h. The markers of fibroblast activation were determined. In order to confirm the anti-fibrosis effect of apigenin, the expression of fibrosis-associated genes in renal fibroblasts was assessed. As a consequence, apigenin alleviated fibroblast proliferation and fibroblastmyofibroblast differentiation induced by TGF-β1. Result: Notably, apigenin significantly inhibited the fibrosis-associated genes expression in renal fibroblasts. Moreover, apigenin treatment significantly increased the phosphorylation of AMP-activated protein kinase (AMPK). Apigenin treatment also obviously reduced TGF-β1 induced phosphorylation of ERK1/2 but not Smad2/3, p38 and JNK MAPK in renal fibroblasts. Conclusion: In a summary, these results indicate that apigenin inhibits renal fibroblast proliferation, differentiation and function by AMPK activation and reduced ERK1/2 phosphorylation, suggesting it could be an attractive therapeutic potential for the treatment of renal fibrosis.

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Bone marrow-derived progenitor cells and renal fibrosis

Frontiers in Bioscience ◽

10.2741/3072 ◽

2008 ◽

Vol Volume (13) ◽

pp. 5163 ◽

Cited By ~ 7

Author(s):

Volha Ninichuk

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Renal Fibrosis

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microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02083-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Zhou ◽

Yang Lin ◽

Xiuhua Kang ◽

Zhicheng Liu ◽

Wei Zhang ◽

...

Keyword(s):

Bone Marrow ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Extracellular Vesicles ◽

Luciferase Assay ◽

Therapeutic Effects ◽

Loss Of Function ◽

Fibroblast Activation ◽

Promising Therapeutic Approach

Abstract Background Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model. Methods In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1). Results BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1. Conclusion In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

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Effects of Bone Marrow Mesenchymal Stem Cells on Plasminogen Activator Inhibitor-1 and Renal Fibrosis in Rats with Diabetic Nephropathy

Archives of Medical Research ◽

10.1016/j.arcmed.2016.03.002 ◽

2016 ◽

Vol 47 (2) ◽

pp. 71-77 ◽

Cited By ~ 16

Author(s):

Hong Lang ◽

Chun Dai

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Diabetic Nephropathy ◽

Plasminogen Activator ◽

Renal Fibrosis ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Marrow Mesenchymal Stem Cells ◽

Activator Inhibitor

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Blocking the Class I Histone Deacetylase Ameliorates Renal Fibrosis and Inhibits Renal Fibroblast Activation via Modulating TGF-Beta and EGFR Signaling

PLoS ONE ◽

10.1371/journal.pone.0054001 ◽

2013 ◽

Vol 8 (1) ◽

pp. e54001 ◽

Cited By ~ 85

Author(s):

Na Liu ◽

Song He ◽

Li Ma ◽

Murugavel Ponnusamy ◽

Jinhua Tang ◽

...

Keyword(s):

Histone Deacetylase ◽

Renal Fibrosis ◽

Class I ◽

Tgf Beta ◽

Egfr Signaling ◽

Fibroblast Activation

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Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy381 ◽

2018 ◽

Vol 34 (10) ◽

pp. 1657-1668 ◽

Cited By ~ 4

Author(s):

Ying Yang ◽

Xiaojian Feng ◽

Xinyan Liu ◽

Ying Wang ◽

Min Hu ◽

...

Keyword(s):

Bone Marrow ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Kidney Diseases ◽

Unilateral Ureteral Obstruction ◽

Immunofluorescent Staining ◽

Enzyme Linked Immunosorbent Assay ◽

Pathological Feature ◽

Kidney Fibrosis ◽

Anti Inflammatory

AbstractBackgroundRenal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage–myofibroblast transition (MMT) in renal fibrosis.MethodsTGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.ResultsInhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.ConclusionsOur results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

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