scholarly journals Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Shan-Shan Li ◽  
Qian Sun ◽  
Meng-Ru Hua ◽  
Ping Suo ◽  
Jia-Rong Chen ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Renal Fibrosis ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Treatment Strategies ◽  
Plasminogen Activator Inhibitor 1 ◽  
Renal Interstitial Fibrosis ◽  
Renal Tubulointerstitial Fibrosis

The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

scholarly journals HuangQi Decoction Improves Renal Tubulointerstitial Fibrosis in Mice by Inhibiting the Up-Regulation of Wnt/β-Catenin Signaling Pathway

2015 ◽  
Vol 36 (2) ◽  
pp. 655-669 ◽  
Author(s):  
Ming-Qian Jiang ◽  
Li Wang ◽  
Ai-li Cao ◽  
Jie Zhao ◽  
Xia Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sham Group ◽  
Interstitial Fibrosis ◽  
Immunohistochemical Analysis ◽  
Tubulointerstitial Fibrosis ◽  
Rt Pcr ◽  
Renal Interstitial Fibrosis ◽  
Expression Levels ◽  
Renal Tubulointerstitial Fibrosis ◽  
Gsk 3Β

Object: To explore the effects of HuangQi decoction on tubulointerstitial fibrosis in mice and the Wnt/β-catenin signaling pathway. Methods: Unilateral ureteral obstruction (UUO) model was used. A total of 120 C57/BL mice were randomly divided into 6 groups, sham group, sham+HuangQi decoction group (1.08 g/kg), UUO group, UUO+HuangQi decoction group (0.12, 0.36, 1.08 g/kg). Immunohistochemical analysis, RT-PCR and Western blot were employed to examine the proteins and genes related to the Wnt/β-catenin signaling pathway. Results: In UUO mice models, expression levels of Wnt3,4, Frizzled4, LRP5,6, β-catenin, LEF-1, TCF-1, Snail, MMP2,7 genes were positively correlated with the degree of renal tubulointerstitial fibrosis, while expression levels of GSK-3β, Axin, APC, CK1 were negatively correlated. HuangQi decoction could down-regulate expression levels of Wnt3,4, Frizzled4, LRP5,6, β-catenin, LEF-1, TCF-1, Snail, Twist, MMP2,7 and up-regulate expression levels of GSK-3β, Axin, APC, CK1 and E-cadherin. Conclusion: HuangQi decoction could effectively inhibit the up-regulation of Wnt/β-catenin signaling pathway induced by UUO, implying a possible role in improving renal interstitial fibrosis.

scholarly journals Foxp3-Positive Regulatory T Cells Contribute to Antifibrotic Effects in Renal Fibrosis via an Interleukin-18 Receptor Signaling Pathway

2020 ◽  
Vol 7 ◽  
Author(s):  
Yasuaki Hirooka ◽  
Yuji Nozaki ◽  
Kaoru Niki ◽  
Asuka Inoue ◽  
Masafumi Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cd4 T Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Renal Interstitial Fibrosis

Renal interstitial fibrosis is a common lesion in the process of various progressive renal diseases. Interleukin (IL)-18 is a proinflammatory cytokine that plays an important role in the induction of Th1 responses and is associated with renal interstitial fibrosis, but the mechanism of fibrosis remains unclear. Here we used IL-18 receptor alpha knockout (IL-18Rα KO) mice to investigate the role of an IL-18Rα signaling pathway in renal fibrosis in a murine model of unilateral ureteral obstruction. IL-18 Rα KO mice showed decreased renal interstitial fibrosis and increased infiltration of CD4+ T cells and Foxp3+ regulatory T cells (Tregs) compared to wildtype (WT) mice. The expression of renal transforming growth factor beta 1 (TGF-β1, which is considered an important cytokine in renal interstitial fibrosis) was not significantly different between WT and IL-18Rα KO mice. The adoptive transfer of CD4+ T cells from the splenocytes of IL-18Rα KO mice to WT mice reduced renal interstitial fibrosis and increased the number of Foxp3+ Tregs in WT mice. These results demonstrated that Foxp3+ Tregs have a protective effect in renal interstitial fibrosis via an IL-18R signaling pathway.

LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

2021 ◽  
pp. 1-11
Author(s):  
Ting-Ting Liu ◽  
Ran Luo ◽  
Yi Yang ◽  
Yi-Chun Cheng ◽  
Dan Chang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Tube Formation ◽  
Renal Interstitial Fibrosis ◽  
Genetic Ablation ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries ◽  
Renal Tubular

<b><i>Introduction:</i></b> Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. <b><i>Methods:</i></b> We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. <b><i>Results:</i></b> We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. <b><i>Conclusion:</i></b> LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

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...

scholarly journals Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy

2019 ◽  
Author(s):  
Liming Guo ◽  
Kuibi Tan ◽  
Qun Luo ◽  
Xu Bai
Keyword(s):  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Rat Model ◽  
Interstitial Fibrosis ◽  
Mtor Signaling ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Mtor Signaling Pathway ◽  
Renal Interstitial Fibrosis ◽  
Gene Assay

Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An in vivo DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). In vitro, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.

scholarly journals Signaling Pathways Involved in Diabetic Renal Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuqing Zhang ◽  
De Jin ◽  
Xiaomin Kang ◽  
Rongrong Zhou ◽  
Yuting Sun ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
New Drugs ◽  
Therapeutic Effects ◽  
Renal Interstitial Fibrosis ◽  
Notch Pathways ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

2021 ◽  
Vol 19 (4) ◽  
pp. 508-513
Author(s):  
Jinhao Wu ◽  
Chao Huang ◽  
Gang Kan ◽  
Hanyu Xiao ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Therapeutic Drugs ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Renal Tubular ◽  
Antioxidant Effects ◽  
Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

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.

scholarly journals Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

2020 ◽  
Vol 21 (2) ◽  
pp. 402 ◽  
Author(s):  
Yi Quan ◽  
Woong Park ◽  
Jixiu Jin ◽  
Won Kim ◽  
Sung Kwang Park ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Mitochondrial Dynamics ◽  
Unilateral Ureteral Obstruction ◽  
Sirtuin 3 ◽  
Smad Signaling ◽  
Renal Tubulointerstitial Fibrosis ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3 (SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrial biogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as a pharmaceutical SIRT3 activator, has been observed to have a protective effect against pressure overload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigated whether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubular injury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKL treatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusion through SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might have beneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document