scholarly journals P0735ELAVATED INTRACELLULAR COPPER CONTRIBUTES A UNIQUE ROLE TO KIDNEY FIBROSIS BY LYSYL OXIDASE MEDIATED MATRIX CROSSLINGKING

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yangyang Niu ◽  
Chen Yu
Keyword(s):  
Renal Fibrosis ◽  
Copper Concentration ◽  
Lysyl Oxidase ◽  
Kidney Tissue ◽  
Underlying Mechanism ◽  
Cross Linking ◽  
Tgf Β1 ◽  
Collagen Cross Linking ◽  
Intracellular Copper

Abstract Background and Aims Copper is an essential trace element required for many biological processes. Some studies have demonstrated that copper accumulating was related to liver fibrosis and lung fibrosis, but the underlying mechanism is not very clear. Copper is the essential unit of lysyl oxidase (LOXs), which are the key enzymes of crosslinking of extracellular matrix. Method Sprague-Dawley rats were divided into the sham group, unilateral ureteral obstruction (UUO) operated group and UUO treated with copper chelating agents tetrathiomolybdate (TM). Rat kidney fibroblast cells (NRK-49F) were used in vitro. The concentration of copper, the LOXs activity and the degree of cross-linking of extracellular collagen were detected in vivo and vitro. Results (1) The copper concentration in serum, urine and kidney of rats increased significantly at 7 days after UUO surgery; After treatment of TGF-β1, the intracellular copper concentration was increased significantly in cells; The concentration of copper in patients` serum is on the rise with the progression of chronic kidney disease (CKD). (2) The expression of CTR1 was upregulated in the kidneys of UUO rats; The level of CTR1 was increased significantly by TGF-β1 in vitro; (3) Blockage of Smad2/3 suppresses TGF-β1-induced expression of CTR1; (4) Downregulation of CTR1 significantly inhibited the intracellular copper concentration; (5) The activity of LOXs was increased significantly after TGF-β1 treatment; (6) Downregulation of CTR1 significantly inhibited the activity of LOXs and the cross-linking of extracellular collagen induced by TGF-β1 in vitro; (7) The concentration of copper, the degree of collagen cross-linking and the deposition of collagen were decreased in the kidney tissue of UUO rats after treatment with TM. The concentration of intracellular copper, the activity of LOXs and the degree of collagen cross-linking were attenuated with treatment of TM in vitro. Conclusion We firstly found that the intracellular copper accumulating was closely to renal fibrosis. The underlying mechanism was related with the increasing expression of CTR1 and activity of LOXs. Treatment with TM ameliorated the renal fibrosis. This study presented a novel treatment target for renal fibrosis.

Collagen cross-linking: Lysyl oxidase dependent synthesis of pyridinoline in vitro: Confirmation that pyridinoline is derived from collagen

1982 ◽  
Vol 108 (4) ◽  
pp. 1546-1550 ◽  
Author(s):  
Robert C. Siegel ◽  
Joseph C.C. Fu ◽  
Norihiko Uto ◽  
Kentaro Horiuchi ◽  
Daisaburo Fujimoto
Keyword(s):  
Lysyl Oxidase ◽  
Cross Linking ◽  
Collagen Cross Linking

Apigenin Alleviates Renal Fibroblast Activation through AMPK and ERK Signaling Pathways In Vitro

2020 ◽  
Vol 21 (11) ◽  
pp. 1107-1118
Author(s):  
Ningning Li ◽  
Zhan Wang ◽  
Tao Sun ◽  
Yanfei Lei ◽  
Xianghua Liu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Protective Role ◽  
Fibroblast Proliferation ◽  
Fibroblast Activation ◽  
And Function ◽  
Activated Fibroblasts ◽  
Tgf Β1

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.

scholarly journals The Interactome of Cancer-Related Lysyl Oxidase and Lysyl Oxidase-Like Proteins

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 71
Author(s):  
Sylvain D. Vallet ◽  
Coline Berthollier ◽  
Romain Salza ◽  
Laurent Muller ◽  
Sylvie Ricard-Blum
Keyword(s):  
Protein Folding ◽  
Cancer Progression ◽  
Cellular Response ◽  
Lysyl Oxidase ◽  
Chaperone Activity ◽  
Cross Linking ◽  
Binding Assays ◽  
Vessel Development ◽  
New Interactions

The members of the lysyl oxidase (LOX) family are amine oxidases, which initiate the covalent cross-linking of the extracellular matrix (ECM), regulate ECM stiffness, and contribute to cancer progression. The aim of this study was to build the first draft of the interactome of the five members of the LOX family in order to determine its molecular functions, the biological and signaling pathways mediating these functions, the biological processes it is involved in, and if and how it is rewired in cancer. In vitro binding assays, based on surface plasmon resonance and bio-layer interferometry, combined with queries of interaction databases and interaction datasets, were used to retrieve interaction data. The interactome was then analyzed using computational tools. We identified 31 new interactions and 14 new partners of LOXL2, including the α5β1 integrin, and built an interactome comprising 320 proteins, 5 glycosaminoglycans, and 399 interactions. This network participates in ECM organization, degradation and cross-linking, cell-ECM interactions mediated by non-integrin and integrin receptors, protein folding and chaperone activity, organ and blood vessel development, cellular response to stress, and signal transduction. We showed that this network is rewired in colorectal carcinoma, leading to a switch from ECM organization to protein folding and chaperone activity.

scholarly journals Identification of a microRNA signature in renal fibrosis: role of miR-21

2011 ◽  
Vol 301 (4) ◽  
pp. F793-F801 ◽  
Author(s):  
Abolfazl Zarjou ◽  
Shanzhong Yang ◽  
Edward Abraham ◽  
Anupam Agarwal ◽  
Gang Liu
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Response To Treatment ◽  
Tubular Epithelial Cells ◽  
Altered Expression ◽  
Tnf Α ◽  
Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

scholarly journals Transplantation of Telocytes Attenuates Unilateral Ureter Obstruction-Induced Renal Fibrosis in Rats

2018 ◽  
Vol 46 (5) ◽  
pp. 2056-2071 ◽  
Author(s):  
Long Zheng ◽  
Long Li ◽  
Guisheng Qi ◽  
Mushuang Hu ◽  
Chao Hu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protective Effect ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Kidney Tissue ◽  
Collagen I ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Tgf Β1

Background/Aims: Previous studies imply that telocytes may have a protective effect on fibrosis in various organs, including the liver, colon, and heart. The effect of telocytes on renal fibrosis remains unknown. Herein, this study was designed to investigate the effect of telocytes on renal fibrosis and the potential mechanisms involved. Methods: In a unilateral ureteral obstruction (UUO)-induced renal fibrosis model, telocytes were injected via the tail vein every other day for 10 days. The degree of renal damage and fibrosis was determined using histological assessment. The expression of collagen I, fibronectin, epithelial-mesenchymal transition markers, and Smad2/3 phosphorylation was examined by western blot analyses. Real-time PCR and enzyme-linked immunosorbent assay were performed in vivo to detect the levels of transforming growth factor (TGF)-β1 and various growth factors. Results: Telocytes attenuated renal fibrosis, as evidenced by reduced interstitial collagen accumulation, decreased expression of fibronectin and collagen I, upregulation of E-cadherin, and downregulation of α-smooth muscle actin. Furthermore, telocytes decreased serum TGF-β1 levels, suppressed Smad2/3 phosphorylation, and increased the expression of hepatocyte growth factor (HGF) in rat kidney tissue following UUO. Blockage of HGF counteracted the protective effect of telocytes on UUO-treated kidneys. Through the detection of HGF mRNA levels in vitro, we found that telocytes had no effect on HGF expression compared with renal fibroblasts. Conclusion: Telocytes attenuated UUO-induced renal fibrosis in rats, likely through enhancing the expression of HGF in an indirect manner.

scholarly journals HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1 through ERK1/2 and JNK MAPK pathways

2012 ◽  
Vol 303 (5) ◽  
pp. F757-F765 ◽  
Author(s):  
Hong-bo Xiao ◽  
Rui-hong Liu ◽  
Guang-hui Ling ◽  
Li Xiao ◽  
Yuan-chen Xia ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Underlying Mechanism ◽  
Tissue Type ◽  
Ecm Proteins ◽  
Signaling Events ◽  
Proximal Tubular ◽  
Pai 1

Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-β1-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-β1 would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

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