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

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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Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4+ T Cell Polarization

Stem Cells International ◽

10.1155/2020/2685820 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Zhu Zhu ◽

Chaonan Han ◽

Shuli Xian ◽

Feng Zhuang ◽

Feng Ding ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Cell Infiltration ◽

Inflammatory Factors ◽

Anti Inflammatory

Purpose. Recent evidence has shown that CD4+ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4+ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4+ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4+ T cells in vitro. Materials and Methods. We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4+ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4+ T cells by enzyme-linked immunosorbent assay (ELISA). Results. Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3+ cell infiltration, with a significantly decreased IL17A+CD4+ T cell/CD4+ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4+ T cells were cocultured with PMSCs, CD4+IL17A+ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P<0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P<0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3+/IL-17+ cell infiltration was increased in the kidneys of UUO model animals on day 7. Conclusions. PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4+ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.

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The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model

Bulletin of Taras Shevchenko National University of Kyiv Series Biology ◽

10.17721/1728_2748.2020.80.10-15 ◽

2020 ◽

Vol 80 (1) ◽

pp. 10-15

Author(s):

A. Stavniichuk ◽

O. Savchuk ◽

Abdul Hye Khan ◽

Wojciech K. Jankiewicz ◽

John D. Imig ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Renal Failure ◽

Kidney Disease ◽

Renal Dysfunction ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Control Group ◽

Urea Nitrogen ◽

Kidney Fibrosis

Kidney fibrosis is a key event in the development of chronic kidney disease, leading to end-stage renal failure. Unfortunately, there are now few drugs capable of preventing fibrosis in the kidneys, which is accompanied by the progression of chronic kidney disease in the terminal stage of renal failure. The results show the effectiveness of the use of a new dual-acting agent DM509 in the prevention of renal fibrosis using a model of unilateral obstruction of the ureter in mice. DM509 is both a farnesoid X-receptor agonist and a soluble epoxyhydrolase inhibitor. In this study, there were 8-12 week old C57BL/6J males undergoing surgery, which led to the development of unilateral ureteral obstruction and a control group. Mice received DM509 (10 mg/kg/day) or DM509-free solution together with drinking water for 10 days the day before surgery. Samples of kidney and blood tissues were collected at the end of the experiment. In the unilateral ureteral obstruction group, kidney dysfunction was detected, which was accompanied by increased urea nitrogen content in the blood compared to the control group (63 ± 7 vs. 34 ± 6 mg/d). The reduction of urea nitrogen in the blood by 36 % in mice with unilateral ureteral obstruction treated with DM509 is shown compared to mice with this pathology without treatment, which in turn proved the effectiveness of DM509 in preventing renal dysfunction. In mice with unilateral ureteral obstruction, which did not receive DM509, the development of kidney fibrosis with a high content of hydroxyproline in the kidneys and also increased collagen content in histological sections of the kidneys were detected. In the DM509 group, the renal and collagen hydroxyproline content was 34-66 % lower, indicating the effectiveness of this agent in the treatment of renal fibrosis. Thus, we have shown that the new DM509 is effective in preventing renal dysfunction and renal fibrosis using a murine model of unilateral ureteral obstruction.

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Faculty Opinions recommendation of Akt2 is involved in loss of epithelial cells and renal fibrosis following unilateral ureteral obstruction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718541839.793500897 ◽

2014 ◽

Author(s):

Derek Brazil ◽

Deborah Lavin

Keyword(s):

Epithelial Cells ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction

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CORRIGENDUM: WNT1‐inducible signaling protein‐1 mediates TGF‐β1‐induced renal fibrosis in tubular epithelial cells and unilateral ureteral obstruction mouse models via autophagy

Journal of Cellular Physiology ◽

10.1002/jcp.30469 ◽

2021 ◽

Keyword(s):

Epithelial Cells ◽

Mouse Models ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Tubular Epithelial Cells ◽

Signaling Protein ◽

Tgf Β1

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Selective Targeting of Vascular Endothelial YAP Activity Blocks EndMT and Ameliorates Unilateral Ureteral Obstruction-Induced Kidney Fibrosis

ACS Pharmacology & Translational Science ◽

10.1021/acsptsci.1c00010 ◽

2021 ◽

Author(s):

Yafeng Ren ◽

Yuwei Zhang ◽

Lu Wang ◽

Fuqian He ◽

Mengli Yan ◽

...

Keyword(s):

Ureteral Obstruction ◽

Unilateral Ureteral Obstruction ◽

Vascular Endothelial ◽

Kidney Fibrosis ◽

Selective Targeting

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The antifibrotic and anti-inflammatory effects of icariin on the kidney in a unilateral ureteral obstruction mouse model

Phytomedicine ◽

10.1016/j.phymed.2019.152917 ◽

2019 ◽

Vol 59 ◽

pp. 152917 ◽

Cited By ~ 11

Author(s):

Hsin‐An Chen ◽

Chang-Mu Chen ◽

Siao-Syun Guan ◽

Chih-Kang Chiang ◽

Cheng-Tien Wu ◽

...

Keyword(s):

Mouse Model ◽

Ureteral Obstruction ◽

Unilateral Ureteral Obstruction ◽

Anti Inflammatory

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NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

Mediators of Inflammation ◽

10.1155/2017/8316560 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

Honglei Guo ◽

Xiao Bi ◽

Ping Zhou ◽

Shijian Zhu ◽

Wei Ding

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Mitochondrial Dysfunction ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Tubulointerstitial Fibrosis ◽

Mitochondrial Morphology ◽

Glomerular Injury ◽

Matrix Deposition

Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

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