The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis

Sun, Yu; Qu, Xinli; Caruana, Georgina; Li, Jinhua

doi:10.1016/j.diff.2016.05.008

Cited by 286 publications

(220 citation statements)

References 64 publications

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“…Inagi [51] found that the accumulation of advanced glycation end product (AGE) produces glycative stress closely associated with kidney disease. Various signaling pathways are involved in process of chronic kidney disease, such as Wnt/ β -catenin, TGF- β /Smads, JNK/STAT3, and MAPKs [52]. The common pathway of these renal diseases is tubulointerstitial fibrosis, which is characterized by the superfluous deposition of extracellular matrix, infiltration of lymphocytes, dendritic cells, macrophages [53], and fibroblast proliferation/differentiation.…”

Section: Discussionmentioning

confidence: 99%

iTRAQ‐Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha‐1‐Antitrypsin as Potential Biomarkers

Wei

Huang

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Background. Chronic renal failure (CRF) has become a global health problem and bears a huge economic burden. FuShengong Decoction (FSGD) as traditional Chinese medicine has multiple pharmacological effects. Objectives. To understand the underlying molecular mechanism and signaling pathway involved in the FSGD treatment of CRF and screen differentially expressed proteins in rats with CRF treated with FSGD. Methods. Thirty-three male Sprague-Dawley rats were randomly divided into control group, CRF group, and FSGD group. Differentially expressed proteins were screened by iTRAQ coupled with nanoLC-MS/MS, and these identified proteins were later analyzed by GO, KEGG, and STRING. Additionally, haptoglobin (HP) and alpha-1-antitrypsin (AAT) were finally verified by ELISA, Western blot, and real time PCR. Results. A total of 417 proteins were identified. Nineteen differentially expressed proteins were identified in the FSGD group compared with the model group, of which 3 proteins were upregulated and 16 proteins were downregulated. Cluster analysis indicated that inflammatory response was associated with these proteins and complement and coagulation cascade pathways were predominantly involved. The validation methods further confirmed that the levels of HP and AAT were significantly increased. Conclusions. HP and AAT may be the important biomarkers in the pathogenesis of CRF and FSGD therapy.

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Section: Discussionmentioning

confidence: 99%

iTRAQ‐Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha‐1‐Antitrypsin as Potential Biomarkers

Wei

Huang

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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“…Cellular sources of myofibroblasts generally include resident fibroblasts, tubular epithelial cells, microvascular pericytes, fibrocytes, bone marrow-derived myofibroblasts and endothelial cells [35]. In the tubulointersitium, tubular epithelial cells are the initial site of injury, and then interstitial fibroblasts are activated [9].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

You

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD⁺-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. Methods: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, α-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. Results: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-β1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-β1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-β1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-β1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-β1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. Conclusion: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis.

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“…Recent studies have demonstrated that HG could induce the complex progress of proinflammatory and profibrotic stimuli EMT of tubular epithelial cells in kidneys [16, 17]. Furthermore, the MAPK/ERK and TGF-β/Smad signaling pathways have been reported to play a vital role in the EMT [18, 19]. HG could up-regulate the expression of TGF-β1, which is a strong inducer of EMT in the renal tubular epithelial cells [20].…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Znt7 on High Glucose-Induced Epithelial-to-Mesenchymal Transition in Renal Tubular Epithelial Cells

Zhang

Liang³

et al. 2018

Kidney Blood Press Res

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Background/Aims: Evidence from our and other groups has demonstrated that zinc transporter 7 in SLC30 family (ZnT7) inhibited epithelial-to-mesenchymal transition (EMT) and apoptosis in rat peritoneal mesothelial cells (RPMCs) under high glucose (HG) concentration. In the present study, we investigated the effect of ZnT7 on EMT of renal tubular epithelial cells (RTECs) in an in vitro model of diabetic nephropathy (DN). Methods: A dual-fluorescent staining protocol was used for detection of ZnT7 in a normal rat kidney tubular epithelial cell line (NRK-52E cells). EMT was induced with HG (30 mM). NRK-52E cells were transfected with plasmids codifying for hZnT7-EGFP and interfering RNA for determination of the effect of ZnT7 over-expression and silencing, respectively. Expression of ZnT7, activation of the MAPK/ERK and TGF-β/Smad pathways were analyzed with by means of Western blot. Results: ZnT7 was localized in the perinuclear region and Golgi apparatus. In HG-induced EMT of NRK-52E cells, ZnT7 was up-regulated. Over-expression of ZnT7 led to inhibition of HG-induced EMT, while knock-down of ZnT7 increased EMT. Furthermore, knock-down of ZnT7 and increased HG-induced EMT was accompanied by activation of the MAPK/ERK and TGF-β/Smad pathways. Conclusion: The present study provides evidence that ZnT7 has a protective effect over EMT of RTECs in DN and suggests that the inhibition of HG-induced EMT may be achieved through the MAPK/ERK and TGF-β/Smad pathways. Thereby, ZnT7 could be a potential target for translation medicine and prevention program in DN.

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The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis

Cited by 286 publications

References 64 publications

iTRAQ‐Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha‐1‐Antitrypsin as Potential Biomarkers

iTRAQ‐Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha‐1‐Antitrypsin as Potential Biomarkers

Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2

Protective Effect of Znt7 on High Glucose-Induced Epithelial-to-Mesenchymal Transition in Renal Tubular Epithelial Cells

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