Targeting lysine‐specific demethylase 1A inhibits renal epithelial–mesenchymal transition and attenuates renal fibrosis

2021 ◽  
Vol 36 (1) ◽  
Author(s):  
Xiaoqin Zhang ◽  
Linda Xiaoyan Li ◽  
Chen Yu ◽  
Karl A. Nath ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Lysine Specific Demethylase

Lysine-specific demethylase 1 induced epithelial–mesenchymal transition and promoted renal fibrosis through Jagged-1/Notch signaling pathway

2021 ◽  
pp. 096032712110387
Author(s):  
Huali Zhang ◽  
Jiaming Xing ◽  
Lingwei Zhao
Keyword(s):  
Cell Invasion ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Notch 1 ◽  
Mesenchymal Transition ◽  
Lysine Specific Demethylase ◽  
Tgf Β1 ◽  
E Cadherin

Objective TGF-β1-induced excessive deposition of extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) process of tubular epithelial cells play critical roles in the progression of renal fibrosis. We are aimed to explore the effects of lysine-specific demethylase 1 (LSD1) in TGF-β1-treated HK-2 cells and in rats with unilateral ureteral obstruction (UUO), and to investigate the underlying molecular mechanism. Methods TGF-β1-treated HK-2 cells and UUO-treated rats were used to establish the model of renal fibrosis in vitro and in vivo, respectively. Protein expression of LSD1, E-cadherin, a-smooth muscle actin (a-SMA), Vimentin, Jagged-1, Notch-1 and Notch-2 were detected by Western blot. The concentrations of type I collagen (Col-I) and Fibronectin (FN) were measured by ELISA. Transwell assay were used to assess cell invasion. Results LSD1 was dramatically increased in TGF-β1-stimulated HK-2 cells. Knockdown of LSD1 decreased the TGF-β1-induced secretion of Col-I and FN, and suppressed TGF-β1-induced expression of E-cadherin,α-SMA and Vimentin, while suppressed cell invasion. Consistent with the in vitro data, the severe histopathological damage, collagen deposition and reduced E-cadherin, increased α-SMA induced by UUO was abated by the knockdown of LSD1 in vivo. Moreover, knockdown of LSD1 suppressed TGF-β1-induced expression of Jagged-1, Notch-1 and Notch-2. Furthermore, we found that inhibition of Notch signaling by a γ-secretase inhibitor RO4929097 almost recapitulated the effects of LSD1 knockdown in TGF-β1-induced HK-2 cells, and at least in part reversed the effects of LSD1 overexpression on EMT and ECM deposition in HK-2 cells. Conclusions Taken together, LSD1 significantly impact on the progression of TGF-β1-mediated EMT and ECM deposition in HK-2 cells, and it may represent novel target for the prevention strategies of renal fibrosis.

Carvacrol Ameliorates Transforming Growth Factor-β1-Induced Extracellular Matrix Deposition and Reduces Epithelial-Mesenchymal Transition by Regulating The Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway In Hk-2 Cells

2021 ◽  
Vol 19 (4) ◽  
pp. 501-507
Author(s):  
Yunhe Gu ◽  
Peiyao Guo ◽  
Guangbiao Xu
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition ◽  
Dose Dependent

Transforming growth factor-β1 promotes excessive extracellular matrix deposition and epithelial-mesenchymal transition of tubular epithelial cells, thus stimulating the progression of renal fibrosis. Carvacrol has been shown to alleviate cardiac and liver fibrosis and attenuate renal injury. However, the role of carvacrol on renal fibrosis has not been examined. First, measurements using Cell Counting Kit-8 showed that carvacrol reduced cell viability of tubular epithelial cell line HK-2 in a dose-dependent fashion. Second, transforming growth factor-β1 induced excessive extracellular matrix deposition in HK-2 cells with enhanced collagen I, collagen IV, and fibronectin expression. However, carvacrol decreased the expression of collagen I, collagen IV in a dose-dependent manner and fibronectin to attenuate the extracellular matrix deposition in HK-2. Third, carvacrol attenuated TGF-β1-induced decrease of E-cadherin and increase of snail, vimentin, and alpha-smooth muscle actin in HK-2 cells. Transforming growth factor-β1-induced increase in PI3K and AKT phosphorylation in HK-2 were also reversed by carvacrol. Collectively, carvacrol ameliorates renal fibrosis through inhibition of transforming growth factor-β1-induced extracellular matrix deposition and epithelial-mesenchymal transition of HK-2 cells, providing potential therapy for the treatment of renal fibrosis.

scholarly journals The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Weiwei Liu ◽  
Yang Yi ◽  
Chuanfu Zhang ◽  
Baojuan Zhou ◽  
Lin Liao ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Mtor Pathway ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Mtorc1 Pathway ◽  
Hk2 Cells

Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.

MiR-32-5p knockdown inhibits epithelial to mesenchymal transition and renal fibrosis by targeting SMAD7 in diabetic nephropathy

2020 ◽  
pp. 096032712095215
Author(s):  
H-J Wang ◽  
H Liu ◽  
Y-H Lin ◽  
S-J Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Tubular Atrophy ◽  
Mesenchymal Transition ◽  
Gene Assay

Diabetic nephropathy (DN) is primary cause of end-stage renal disease. A previous study has shown that miR-32-5p (miR-32) is highly expressed in kidney tissue during chronic allograft dysfunction with interstitial fibrosis and tubular atrophy. However, the role of miR-32-5p (miR-32) in DN is still unclear. In this study, streptozotocin-induced DN rat models and high glucose (HG)-incubated human kidney proximal tubular epithelial (HK-2) cells were established to investigate the role and underlying mechanisms of miR-32 in DN. Results of real-time PCR revealed that miR-32 levels were greatly increased in DN rats and HG-incubated HK-2 cells. Downregulation of miR-32 effectively relieved HG-induced autophagy suppression, fibrosis, epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells. Besides, miR-32 overexpression significantly down-regulated the expression of mothers against decapentaplegic homolog 7 (SMAD7), whereas knockdown of miR-32 markedly up-regulated the level of SMAD7. Dual-luciferase reporter gene assay confirmed that SMAD7 was a target of miR-32. Reintroduction of SMAD7 expression rescued miR-32-induced HK-2 cells autophagy suppression, EMT and renal fibrosis. Our findings indicate that miR-32 may play roles in the progression of EMT and fibrosis in DN.

P0014MYELOID-SPECIFIC TARGETING OF NOTCH AMELIORATES RENAL FIBOSIS VIA REDUCED INFILTRATION AND ACTIVATION OF BONE MARROW-DERIVED MACROPHAGE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yali Jiang
Keyword(s):  
Bone Marrow ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Specific Targeting ◽  
Ccr2 Expression ◽  
Extracellular Matrix Deposition ◽  
Novel Strategy ◽  
Underlying Mechanisms

Abstract Background and Aims Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. Method In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Results Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. Conclusion In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.

scholarly journals IL-18 neutralization ameliorates obstruction-induced epithelial–mesenchymal transition and renal fibrosis

2009 ◽  
Vol 76 (5) ◽  
pp. 500-511 ◽  
Author(s):  
Ahmad H. Bani-Hani ◽  
Jeffery A. Leslie ◽  
Hiroshi Asanuma ◽  
Charles A. Dinarello ◽  
Matthew T. Campbell ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals Effect of Huai Qi Huang on Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells through miR-200a

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jinyun Pu ◽  
Yu Zhang ◽  
Jianhua Zhou
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanism ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Renal Tubular

Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells is a vital mechanism of renal fibrosis. Mounting evidence suggests that miR-200a expression decreases in tubular epithelial cells in unilateral ureteral obstruction (UUO) rats. Moreover, it has been demonstrated that Huai Qi Huang (HQH) can ameliorate tubulointerstitial damage in adriamycin nephrosis and delay kidney dysfunction in primary glomerular disease. However, the effect of HQH on EMT of tubular epithelial cells in UUO rats and its molecular mechanism is unclear. In order to explore the effect of HQH on EMT and its molecular mechanism in renal fibrosis,in vitroandin vivoexperiments were performed in our study. Our results showed that HQH increased miR-200a expression in UUO rats and in TGF-β1 stimulated NRK-52E cells. Meanwhile, HQH decreased ZEB1 and ZEB2 (the transcriptional repressors of E-cadherin),α-SMA expression in renal tubular epithelial cellsin vitroandin vivo. Furthermore, we found that HQH protected kidney from fibrosis in UUO rats. The results demonstrated that HQH regulated miR-200a/ZEBs pathway and inhibited EMT process, which may be a mechanism of protecting effect on tubular cells in renal fibrosis.

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