scholarly journals A Novel Inhibitor of Homodimerization Targeting MyD88 Ameliorates Renal Interstitial Fibrosis by Counteracting TGF-β1-Induced EMT in Vivo and in Vitro

2018 ◽  
Vol 43 (5) ◽  
pp. 1677-1687 ◽  
Author(s):  
Jian-Hua Liu ◽  
Long He ◽  
Zhi-Miao Zou ◽  
Zuo-Chuan Ding ◽  
Xue Zhang ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Renal Interstitial Fibrosis ◽  
Tgf Β1

scholarly journals SKLB023 hinders renal interstitial fibrosis in obstructive nephropathy by interfering TGF-β1/Smad3 signaling

RSC Advances ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 5891-5896 ◽  
Author(s):  
Yanhuan Feng ◽  
Jun Xu ◽  
Fan Guo ◽  
Rongshuang Huang ◽  
Min Shi ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Therapeutic Strategy ◽  
Interstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
The Novel ◽  
Renal Interstitial Fibrosis ◽  
Molecule Inhibitor ◽  
Tgf Β1

The novel small-molecule inhibitor of iNOS (SKLB023) hindered renal interstitial fibrosis in vivo and in vitro by interfering with TGF-β1/Smad3 signaling, highlighting that SKLB023 has potential in the therapeutic strategy for renal fibrosis.

Apamin inhibits renal interstitial inflammation and fibrosis via suppressing TGF-β1 and STAT3 signaling pathway in vivo and in vitro

2020 ◽  
Author(s):  
Mi-Gyoeng Gwon ◽  
Hyun-Jin An ◽  
Hyemin Gu ◽  
Young-Ah Kim ◽  
Sang Mi Han ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Renal Interstitial Fibrosis ◽  
Tubular Atrophy ◽  
Fibroblast Activation ◽  
Stat3 Signaling ◽  
Tgf Β1

Abstract Background Renal fibrosis is a progressive and chronic process that influences kidneys with chronic kidney disease (CKD), irrespective of cause, leading to irreversible failure of renal function and end-stage kidney disease. Among the signaling related to renal fibrosis, transforming growth factor-β1 (TGF-β1) signaling is a major pathway that induces the activation of myofibroblasts and the production of extracellular matrix (ECM) molecules. Apamin, a component of bee venom (BV), has been studied in relation to various diseases. However, the effect of apamin on renal interstitial fibrosis has not been investigated. The aim of this study was to estimate the beneficial effect of apamin in unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-β1-induced renal fibroblast activation.Results This study revealed that obstructive kidney injury induced an inflammatory response, tubular atrophy, and ECM accumulation. However, apamin treatment suppressed the increased expression of fibrotic-related genes, including α-SMA, vimentin, and fibronectin. Administration of apamin also attenuated the renal tubular cells injury and tubular atrophy. In addition, apamin attenuated fibroblast activation, ECM synthesis, and inflammatory cytokines such as TNF-α, IL-1β and IL-6 by suppressing the TGF-β1-canonical and non-canonical signaling pathways.Conclusions This study shown that apamin inhibites UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibroblasts activation in vitro. Apamin inhibited the inflammatory response, tubular atrophy, ECM accumulation, fibroblast activation, and renal interstitial fibrosis through suppression of TGF-β1/Smad2/3 and STAT3 signaling pathways. These results suggest that apamin might be a potential therapeutic agent for renal fibrosis.

scholarly journals Salidroside Ameliorates Renal Interstitial Fibrosis by Inhibiting the TLR4/NF-κB and MAPK Signaling Pathways

2019 ◽  
Vol 20 (5) ◽  
pp. 1103 ◽  
Author(s):  
Rui Li ◽  
Yujuan Guo ◽  
Yiming Zhang ◽  
Xue Zhang ◽  
Lingpeng Zhu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Mapk Signaling ◽  
Renal Interstitial Fibrosis ◽  
Mapk Signaling Pathways ◽  
Tgf Β1

Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.

Fucoidans from Cucumaria frondosa ameliorates renal interstitial fibrosis via inhibition of PI3K/Akt/NF-κB signaling pathway

2022 ◽  
Author(s):  
Zhuo-yue Song ◽  
Mengru Zhu ◽  
Jun Wu ◽  
Tian Yu ◽  
Yao Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Protein Kinase B ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Renal Interstitial Fibrosis ◽  
Cucumaria Frondosa

The effects of Cucumaria frondosa polysaccharides (CFP) on renal interstitial fibrosis via regulating phosphatidylinositol-3-hydroxykinase/protein kinase-B/Nuclear factor-κB (PI3K/AKT/NF-κB) signaling pathway were investigated in vivo and in vitro in this research. A...

Pterostilbene, a Bioactive Component of Blueberries, Alleviates Renal Interstitial Fibrosis by Inhibiting Macrophage-Myofibroblast Transition

2020 ◽  
Vol 48 (07) ◽  
pp. 1715-1729
Author(s):  
Yanhuan Feng ◽  
Fan Guo ◽  
Hongxia Mai ◽  
Jing Liu ◽  
Zijing Xia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Fibrosis ◽  
Transcriptional Activity ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Rna Seq ◽  
Renal Interstitial Fibrosis ◽  
Bioactive Component

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the in vivo mouse unilateral ureteral obstruction (UUO) model and in vitro MMT cells. Kidneys subjected to UUO with PTB treatment were collected for the investigation of PTB mediating MMT derived renal interstitial fibrosis. We conducted kidney RNA-seq transcriptomes and TGF-[Formula: see text]1-induced bone marrow-derived macrophages assays to determine the mechanisms of PTB. We found that PTB treatment suppressed the interstitial fibrosis in UUO mice. PTB also attenuated the number of MMT cells in vivo and in vitro. The transcriptomic analysis showed that CXCL10 may play a central role in the process of PTB-treated renal fibrosis. The siRNA-mediated CXCL10 knockdown decreased the number of MMT cells in TGF-[Formula: see text]1-induced bone marrow-derived macrophages. Our results suggested that PTB attenuated renal interstitial fibrosis by mediating MMT by regulating transcriptional activity of CXCL10.

scholarly journals GSTA3 regulates TGF-β1-induced renal interstitial fibrosis in NRK-52E cells as a component of the PI3K–Keap1/Nrf2 pathway

2019 ◽  
Vol 47 (11) ◽  
pp. 5787-5801
Author(s):  
Yun Xiao ◽  
Zhiwei Zhang ◽  
Yingyu Fu ◽  
Huizhi Shan ◽  
Sini Cui ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Mapk Pathway ◽  
Mrna Levels ◽  
Renal Interstitial Fibrosis ◽  
Nrf2 Pathway ◽  
Nrf2 Signaling Pathway ◽  
Nrf2 Expression ◽  
Tgf Β1

Objective To evaluate the effect of GSTA3 within the PI3K–Keap1/Nrf2 pathway in renal interstitial fibrosis (RIF). Methods An in vitro RIF model with TGF-β1 stimulation in NRK-52E cells was established to identify potential signaling pathways that modulate GSTA3. Changes in GSTA3 expression were observed in the RIF model after silencing or enhancing Nrf2 expression. Changes in GSTA3, Keap1, and Nrf2 expression were detected after blocking the upstream of the Keap1/Nrf2 signaling pathway (including MAPK and PI3K/Akt). The effect of Nrf2 on GSTA3 expression was evaluated by overexpressing Nrf2. Results Protein and mRNA levels of GSTA3, FN, Nrf2, and Keap1 were significantly increased after TGF-β1 stimulation. GSTA3 was also upregulated following overexpression of Nrf2. TGF-β1 activated the PI3K/Akt signaling pathway, leading to RIF. After blocking this pathway, the production of superoxide dismutase, reactive oxygen species, and fibronectin were reduced. The MAPK pathway was not involved in the development of RIF via regulating GSTA3 expression. Conclusions The PI3K–KEAP1/Nrf2–GSTA3 signaling pathway is a possible mechanism of resisting external stimulation of renal fibrosis factors, regulating oxidative stress, and preventing RIF.

Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice

2016 ◽  
Vol 130 (19) ◽  
pp. 1727-1739 ◽  
Author(s):  
Akiko Tanino ◽  
Takafumi Okura ◽  
Tomoaki Nagao ◽  
Masayoshi Kukida ◽  
Zuowei Pei ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Rat Kidney ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Renal Interstitial Fibrosis

Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18−/− and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.

Mice with Megakaryocyte-Specific Deletion of TGF-β1 Are Partially Protected From Developing Cardiac Fibrosis and Systolic Dysfunction in a Pressure Overload Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 362-362
Author(s):  
Alexander Meyer ◽  
Wei Wang ◽  
Jay L. Degen ◽  
Barry S. Coller ◽  
Jasimuddin Ahamed
Keyword(s):  
Shear Force ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Heart Weight ◽  
Tgf Β1 ◽  
Specific Deletion ◽  
Severe Fibrosis

Abstract Abstract 362 Circulating platelets contain a high concentration of the multifunctional cytokine transforming growth factor-β1 (TGF-β1) in their α-granules and release it as an inactive (latent) complex upon platelet adhesion and/or activation. We recently demonstrated that shear force can activate latent TGF-β1 in vitro, and this mechanism may contribute to the activation of TGF-β1 that we observed in vivo in the carotid arteries following injury and thrombus formation. TGF-β1 is reported to be involved in the development of cardiac fibrosis in both humans and mouse models, but the cellular source(s) of TGF-β1 and its activation mechanism in vivo have not been clearly established. To test the hypothesis that platelet TGF-β1 contributes to cardiac fibrosis, we performed comparative studies of WT mice and gene-targeted animals with a megakaryocyte-specific deletion of TGF-β1 [PF4-Cre/Tgfb1flox (Tgfb1flox)] using the transverse aortic constriction (TAC) model in male C57Bl/6 mice. Both groups also underwent sham surgery as controls. We obtained blood by percutaneous puncture of the LV under ultrasound guidance and plasma samples were prepared by immediate centrifugation at 12,000 g for 5 min. This technique consistently results in plasma TGF-β1 levels in the range of ∼1.0 ng/ml, which are below those previously reported by most investigators. Tgfb1flox mice had 45% lower levels of plasma total TGF-β1 than WT animals, with a median total TGF-β1 level in WT of 1.37 ng/ml (IQR, interquartile range, 1.2–1.6; n=45) compared to 0.76 ng/ml (IQR 0.6–0.9; n=25)] in Tgfb1flox mice (p<0.001). Heart weight/body weight ratios were 42% higher in TAC- (n=15) than in sham- (n=16) operated WT mice (p<0.001) after 4 weeks, but only 11% higher in TAC- (n=13) than sham- (n=12) operated Tgfb1flox mice (p=0.02). The heart weight/body weight ratios correlated with total TGF-β1 levels in WT mice undergoing both sham and TAC surgery (r=0.66; p<0.001), but not in Tgfb1flox mice. Cardiac fibrosis was scored 4 weeks after surgery by an expert veterinary pathologist as 0 for no fibrosis, and 1+, 2+, or 3+ for mild, moderate, and severe fibrosis, respectively. 96% (22/23) of WT mice developed interstitial fibrosis after TAC, with 65% (15/23) developing mild and 30% (7/23) developing moderate (6/23) or severe (1/23) fibrosis. In contrast, only 54% (7/13) of Tgfb1flox mice developed interstitial fibrosis, with 31% (4/13) developing mild and 15% (2/13) developing moderate fibrosis; none developed severe fibrosis (p<0.01). The Tgfb1flox mice also had significantly less perivascular fibrosis than did the WT mice, although the differences were less evident (p=0.03). Cardiac function measured by echocardiography one week after TAC surgery demonstrated that Tgfb1flox mice had better systolic function than WT mice (Table).Table:Cardiac function measurements one week after TAC surgery.WTTgfb1flox†pEF [%]41 [37–48; n=11]56 [48–65; n=11]0.03SV [μl]20 [18–21; n=11]28 [24–33; n=11]0.003FS (%)27 [23–30; n=14]32 [28–37; n=13]0.05EF: ejection fraction; SV: stroke volume; FS: fractional shortening. Data are reported as median [IQR] †Wilcoxon Rank-Sum test. Presurgery values for EF, SV, and FS were similar in WT and Tgfb1flox mice We conclude that platelet TGF-β1 contributes to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction induced by a high shear, TAC model. These data have important implications for understanding TGF-β1 biology and assessing the role of TGF-β1 in murine models of human diseases. Since shear can dramatically activate TGF-β1 in vitro, it is possible that increased shear force in the TAC mice generates active TGF-β1, which may contribute to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals miR-382 Contributes to Renal Tubulointerstitial Fibrosis by Downregulating HSPD1

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Yi Fang ◽  
Ting Xie ◽  
Ning Xue ◽  
Qing Kuang ◽  
Zheng Wei ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
In Vitro Study ◽  
Human Kidney ◽  
Tubulointerstitial Fibrosis ◽  
Heat Shock Protein 60 ◽  
Renal Interstitial Fibrosis ◽  
Redox Imbalance ◽  
Renal Tubulointerstitial Fibrosis

Redox imbalance plays an important role in the pathogenesis of CKD progression. Previously, we demonstrated that microRNA-382 (miR-382) contributed to TGF-β1-induced loss of epithelial polarity in human kidney epithelial cells, but its role in the development of renal tubulointerstitial fibrosis remains unknown. In this study, we found that with 7 days of unilateral ureteral obstruction (UUO) in mice, the abundance of miR-382 in the obstructed kidney was significantly increased. Meanwhile, the protein expression of heat shock protein 60 (HSPD1), a predicted target of miR-382, was reduced after 7 days of UUO. Expression of 3-nitrotyrosine (3-NT) was upregulated, but expression of thioredoxin (Trx) was downregulated. Anti-miR-382 treatment suppressed the upregulation of miR-382, attenuated renal interstitial fibrosis in the obstructed kidney, and reversed the downregulation of HSPD1/Trx and upregulation of 3-NT after UUO. Furthermore, in vitro study revealed that overexpression of HSPD1 significantly restored Trx expression and reversed TGF-β1-induced loss of E-cadherin, while in vivo study found that direct siRNA-mediated suppression of HSPD1 in the UUO kidney promoted oxidative stress despite miR-382 blockade. Our clinical data showed that upregulation of miR-382/3-NT and downregulation of HSPD1/Trx were also observed in IgA nephropathy patients with renal interstitial fibrosis. These data supported a novel mechanism in which miR-382 targets HSPD1 and contributes to the redox imbalance in the development of renal fibrosis.

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