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.

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.

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 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.

scholarly journals Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Haofeng Zheng ◽  
Yannan Zhang ◽  
Jiannan He ◽  
Zhe Yang ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tubulointerstitial Fibrosis ◽  
Health Concern ◽  
Dependent Manner ◽  
Renal Tubulointerstitial Fibrosis

Chronic kidney disease (CKD), which is associated with high morbidity, remains a worldwide health concern, while effective therapies remain limited. Hydroxychloroquine (HCQ), which mainly targets toll-like receptor-7 (TLR-7) and TLR-9, is associated with a lower risk of incident CKD. Taking into account that TLR-9 is involved in the development of renal fibrosis and serves as a potential therapy target for CKD, we investigated whether HCQ could attenuate CKD via TLR-9 signal pathway. The effects of HCQ on renal tubulointerstitial fibrosis were further explored using a mouse model of renal tubulointerstitial fibrosis after ischemia/reperfusion injury. Bone marrow-derived macrophages were isolated to explore the effects of HCQ in vitro. Judicious use of HCQ efficiently inhibited the activation of macrophages and MAPK signaling pathways, thereby attenuating renal fibrosis in vivo. In an in vitro model, results showed that HCQ promoted apoptosis of macrophages and inhibited activation of macrophages, especially M2 macrophages, in a dose-dependent manner. Because TLR-7 is not involved in the development of CKD post-injury, a TLR-9 knockout mouse was used to explore the mechanisms of HCQ. The effects of HCQ on renal fibrosis and macrophages decreased after depletion of TLR-9 in vivo and in vitro. Taken together, this study indicated that proper use of HCQ could be a new strategy for anti-fibrotic therapy and that TLR-9 could be a potential therapeutic target for CKD following acute kidney injury.

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 Metformin Attenuates Renal Tubulointerstitial Fibrosis via Upgrading Autophagy in the Early Stage of Diabetic Nephropathy

2021 ◽  
Author(s):  
Fengzhen Wang ◽  
Dong Sun ◽  
Haihan Sun ◽  
Bangjie Zuo ◽  
Kun Shi ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Early Stage ◽  
Renal Tissue ◽  
Tubulointerstitial Fibrosis ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis

Abstract The aim of the study was to compare the role of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluate its mechanism in high-glucose-treated Renal tubular epithelial cells (RTECs) in vitro. Sprague-Dawley (SD) rats were used to establish model of DN, then the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified via histological analysis, immunohistochemistry, and immunoblot. The underlying relationship between autophagy and DN was analyzed and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) was detected. Metformin markedly improved renal function and showed histological restoration of renal tissues especially in the early stage of DN, with a significant improvement of autophagy and a low expression of fibrotic biomarkers (Fibronectin and Collagen I) in renal tissue. RTECs under hyperglycemic conditions exhibited inactivation of p-AMPK and activation of EMT. But the promotion of AMPK activated by metformin significantly improved renal autophagic function, inhibited the EMT of RTECs, attenuated TIF, so as to effectively prevent or delay the course of DN. This evidence provided theoretical and experimental basis for the following research on the potential clinical usefulness of metformin for the treatment of diabetic TIF.

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.

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