Febuxostat Prevents Renal Interstitial Fibrosis by the Activation of BMP-7 Signaling and Inhibition of USAG-1 Expression in Rats

2015 ◽  
Vol 42 (5) ◽  
pp. 369-378 ◽  
Author(s):  
Jing Cao ◽  
Yong Li ◽  
Yingxian Peng ◽  
Yaqian Zhang ◽  
Huanhuan Li ◽  
...  
Keyword(s):  
Renal Function ◽  
Western Blotting ◽  
Sham Group ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
High Dose ◽  
Renal Interstitial Fibrosis ◽  
Xanthine Oxidase Inhibitor ◽  
Tgf Β1

Background: Renal interstitial fibrosis (RIF) is a common pathology associated with end-stage renal diseases. The activation of bone morphogenetic protein-7 (BMP-7)-Smad1/5/8 pathway seems to alleviate RIF. Uterine sensitization-associated gene-1 (USAG-1), a kidney-specific BMPs antagonist, is associated with the development and prognosis of several renal diseases. Febuxostat is a xanthine oxidase inhibitor that can attenuate the renal dysfunction of patients. The purpose of this study was to investigate the effects of febuxostat on renal fibrosis and to clarify the mechanisms underlying these effects. Methods: Rats were randomly divided into 6 groups termed a sham-operated group, a unilateral ureteral obstruction (UUO) group, 3 doses of febuxostat groups (low, intermediate and high doses) and a sham group treated with high-dose febuxostat. After 14 days, renal function, relative kidney weight, accumulation of glycogen and collagens were examined by different methods. Expression of α-SMA, transforming growth factor-β1 (TGF-β1), BMP-7 and USAG-1 was detected by western blotting and RT-PCR, respectively. The phosphorylation level of Smad1/5/8 was also quantified by western blotting. Results: The renal function was declined, and large amounts of glycogen and collagens were deposited in the kidneys of UUO rats compared with the rats in the sham group. Besides, expression of α-SMA and USAG-1 in these kidneys was elevated, and the TGF-β1 was also activated, while the BMP-7-Smad1/5/8 pathway was inhibited. Febuxostat reversed the changes stated earlier, exhibiting protective effects on RIF induced by UUO. Conclusion: Febuxostat was able to attenuate RIF caused by UUO, which was associated with the activation of BMP-7-Smad1/5/8 pathway and the inhibition of USAG-1 expression in the kidneys of UUO rats.

scholarly journals Tumor-Suppressing STF cDNA 3 Overexpression Suppresses Renal Fibrosis by Alleviating Anoikis Resistance and Inhibiting the PI3K/Akt Pathway

2021 ◽  
pp. 1-13
Author(s):  
Fei Xiao ◽  
Xinghong Liu ◽  
Yan Chen ◽  
Huanzi Dai
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Cell Model ◽  
Cell Counting ◽  
Akt Pathway ◽  
Renal Interstitial Fibrosis ◽  
Anoikis Resistance ◽  
Matrigel Invasion ◽  
Tgf Β1

<b><i>Background:</i></b> Myofibroblast (MF) activation is the key event of irreversible renal interstitial fibrosis. Anoikis resistance is the hallmark of active MFs, which is conferred by continuous activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway. Our previous study found that tumor-suppressing STF cDNA 3 (TSSC3) enhances the sensitivity of cells to anoikis via the PI3K/Akt pathway. Therefore, we hypothesized that TSSC3 might suppress renal interstitial fibrosis by inducing anoikis via the PI3K/Akt pathway. <b><i>Methods:</i></b> Cell anoikis was induced by the exogenous addition of RGD-containing peptides or by culturing cells in suspension. MFs were established by stimulating HK-2 renal tubular epithelial cells with transforming growth factor beta 1 (TGF-β1). Lentivirus vectors were to construct a TSSC3 overexpression cell model. The effects of TSSC3 on the anoikis, growth, migration, invasion, and contraction of MFs were determined using annexin V-fluorescein isothiocyanate assays, cell counting kit-8 assays, wound healing migration assays, matrigel invasion assays, and collagen-based contraction assays. <b><i>Results:</i></b> The results demonstrated that TGF-β1, simultaneous with the induction of MF differentiation, confers significant protection against anoikis-induced cell death, which could be partly reversed by treatment with the PI3K/Akt pathway inhibitor, LY294002. Moreover, overexpression of TSSC3 obviously impaired cell growth, cell migration, cell invasion, contraction, and anoikis resistance of MFs, and decreased the activity of the PI3K/Akt pathway and the production of extracellular matrix molecules, all of which could be attenuated by treatment with the PI3K/Akt pathway activator, 740Y-P. Taken together, this study suggested that TSSC3 attenuates the anoikis resistance and profibrogenic ability of TGF-β1-induced MF by regulating the PI3K-Akt pathway. <b><i>Conclusion:</i></b> These findings provide a biological basis for further exploration of the therapeutic significance of targeting MF via TSSC3 in 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.

Dexrazoxane Alleviated Doxorubicin-Induced Nephropathy in Rats

Pharmacology ◽  
2022 ◽  
pp. 1-10
Author(s):  
Huihui Hu ◽  
Caipeng Xie ◽  
Zeping Weng ◽  
Pei Yu ◽  
Yuqiang Wang ◽  
...  
Keyword(s):  
Renal Function ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Periodic Acid ◽  
Kidney Tissue ◽  
Tunel Staining ◽  
Protective Effects ◽  
Renal Interstitial Fibrosis ◽  
Alpha Smooth Muscle Actin

<b><i>Introduction:</i></b> Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application of DOX is restricted by its multiple organ toxicity including nephrotoxicity. This study investigated the protective effects and mechanisms of dexrazoxane (DZR) against DOX-induced nephropathy in rats. <b><i>Methods:</i></b> Male Sprague Dawley rats received 2.5 mg/kg DOX once a week for 5 consecutive weeks. 24-h urinary protein and renal function injury biomarkers were determined to evaluate the renal function. Histopathological changes and glomerulosclerosis were examined by hematoxylin and eosin and periodic acid-Schiff staining. The change of renal ultrastructure in the DOX-induced rats was observed by the electron microscopy. The renal apoptosis was detected by TUNEL staining and measured the protein expression of Caspase-3, Bcl-2, and Bax. Renal interstitial fibrosis was determined by Masson staining and immunohistochemistry examination. The levels of vimentin, alpha-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in kidney tissue were detected by Western blot. <b><i>Results:</i></b> DZR pretreatment markedly raised the survival rate and improved the renal dysfunction in DOX-treated rats. DZR ameliorated DOX-induced histopathological lesion of glomerular and tubular and apoptosis. DZR restored the oxidant/antioxidant balance via regulating the levels of MDA, SOD, and TAC. DZR reduced DOX-induced collagen IV deposition and renal interstitial fibrosis and downregulated the fibrosis-related protein expressions of vimentin, α-SMA, and TGF-β1. <b><i>Conclusion:</i></b> Our results suggest DZR exerted its protective effects against DOX-induced nephropathy through inhibition of lipid peroxidation, apoptosis, and fibrosis.

scholarly journals The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

2006 ◽  
Vol 26 (12) ◽  
pp. 4577-4585 ◽  
Author(s):  
Jingmei Lin ◽  
Sanjeevkumar R. Patel ◽  
Min Wang ◽  
Gregory R. Dressler
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Bmp Signaling ◽  
Cell Junctions ◽  
Type I ◽  
Renal Interstitial Fibrosis ◽  
Tgf Β1

ABSTRACT The transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) and TGF-β/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-β but inhibited by BMP7. In this report, the effects of KCP on TGF-β/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-β1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-β1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-β and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-β activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.

scholarly journals Long non-coding (lnc)RNA profiling and the role of a key regulator lnc-PNRC2-1 in the transforming growth factor-β1-induced epithelial–mesenchymal transition of CNE1 nasopharyngeal carcinoma cells

2021 ◽  
Vol 49 (3) ◽  
pp. 030006052199651
Author(s):  
Jie Yang ◽  
Enzi Feng ◽  
Yanxin Ren ◽  
Shun Qiu ◽  
Liufang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nasopharyngeal Carcinoma ◽  
Rna Sequencing ◽  
Western Blotting ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
Mesenchymal Transition ◽  
Emt Markers ◽  
Tgf Β1

Objectives To identify key long non-coding (lnc)RNAs responsible for the epithelial–mesenchymal transition (EMT) of CNE1 nasopharyngeal carcinoma cells and to investigate possible regulatory mechanisms in EMT. Methods CNE1 cells were divided into transforming growth factor (TGF)-β1-induced EMT and control groups. The mRNA and protein expression of EMT markers was determined by real-time quantitative PCR and western blotting. Differentially expressed genes (DEGs) between the two groups were identified by RNA sequencing analysis, and DEG functions were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. EMT marker expression was re-evaluated by western blotting after knockdown of a selected lncRNA. Results TGF-β1-induced EMT was characterized by decreased E-cadherin and increased vimentin, N-cadherin, and Twist expression at both mRNA and protein levels. Sixty lncRNA genes were clustered in a heatmap, and mRNA expression of 14 dysregulated lncRNAs was consistent with RNA sequencing. Knockdown of lnc-PNRC2-1 increased expression of its antisense gene MYOM3 and reduced expression of EMT markers, resembling treatment with the TGF-β1 receptor inhibitor LY2109761. Conclusion Various lncRNAs participated indirectly in the TGF-β1-induced EMT of CNE1 cells. Lnc-PNRC2-1 may be a key regulator of this and is a potential target to alleviate CNE1 cell EMT.

scholarly journals Yiqi Wenyang Fang ameliorates allergic rhinitis through inhibiting inflammatory response and promoting the expression of Foxp3

2016 ◽  
Vol 29 (4) ◽  
pp. 696-706 ◽  
Author(s):  
Jun Shi ◽  
Yu Liu ◽  
Shihai Yan ◽  
Daonan Yan
Keyword(s):  
Allergic Rhinitis ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Pcr Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Sprague Dawley ◽  
Model Control ◽  
Tgf Β1

Allergic rhinitis (AR) is an inflammatory disease with a hypersensitivity response to environmental stimulus. The aim of this study was to evaluate the effect of Yiqi Wenyang Fang (YWF) on AR and investigate the underlying mechanism. A total of 48 female Sprague-Dawley rats were randomly divided into six groups (normal control, model control, YWF at low dose, YWF at median dose, YWF at high dose, and loratadine). Rats were injected with antigen for sensitization. Then, rats in the YWF groups were treated with different dose of YWF for 28 days. Loratadine was used as a positive control. Number of sneezes, degree of runny nose, nasal rubbing movements, and tissue damage were scored. The protein and mRNA expression of Foxp3 were determined by western blot and real time-PCR analysis, respectively. Flow cytometry was used to detect the number of CD4+CD25+Foxp3+ Treg cells. The content of interleukin (IL)-10, transforming growth factor β1 (TGF-β1), IL-13, and IL-4 in the serum were detected by enzyme-linked immunosorbent assay (ELISA). Scores of symptoms were significantly reduced and nasal mucosa damage was alleviated after YWF administration. YWF increased the expression of Foxp3, IL-10, TGF-β1, and number of CD4+CD25+Foxp3+ Treg cells which were reduced by antigen injection. The expression levels of IL-13 and IL-4 were increased after antigen administration while decreased after YWF treatment. YWF may ameliorate AR through inhibiting inflammatory response and promoting Foxp3 expression.

scholarly journals Bone Morphogenetic Protein-2 Antagonizes Renal Interstitial Fibrosis by Promoting Catabolism of Type I Transforming Growth Factor-β Receptors

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 727-740 ◽  
Author(s):  
Yu-Lin Yang ◽  
Yi-Shiuan Liu ◽  
Lea-Yea Chuang ◽  
Jinn-Yuh Guh ◽  
Tao-Chen Lee ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ureteral Obstruction ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Morphogenetic Protein ◽  
Tgf Β1

TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-β1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-β1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-β receptors (TGF-β RI). Moreover, BMP-2 significantly shortened the half-life of TGF-β RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-β RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-β RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-β. We demonstrated that BMP-2 significantly reversed the TGF-β1-induced increase in pSmad2/3 and reversed the TGF-β1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-β RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson’s trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-β RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-β RI and Smads. Bone morphogenetic protein-2 can antagonize TGF-β-inducing cellular fibrosis by intervening post-receptors signaling, thus disclosing an application of therapeutical potential against fibrosis disorders.

The Relevance of Periglomerular Fibrosis in the Evaluation of Routine Needle Core Renal Biopsies

2011 ◽  
Vol 135 (1) ◽  
pp. 117-122
Author(s):  
Joseph Jenkins ◽  
Sergey V. Brodsky ◽  
Anjali A. Satoskar ◽  
Gyongyi Nadasdy ◽  
Tibor Nadasdy
Keyword(s):  
Renal Function ◽  
Renal Biopsy ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Renal Diseases ◽  
Glomerular Sclerosis ◽  
Poor Renal Function ◽  
Renal Biopsies ◽  
Biopsy Report ◽  
Relationship Of

Abstract Context—Renal interstitial fibrosis and, to a lesser extent, sclerotic glomeruli correlate with poor renal function. However, not all nonfunctional glomeruli are sclerotic. Many or most glomeruli with periglomerular fibrosis, while retaining blood flow, probably do not filter; therefore, they may not contribute to renal function. Objective—To examine the relationship of periglomerular fibrosis and the sum of globally sclerotic glomeruli and glomeruli with periglomerular fibrosis (GSG+PF) with interstitial fibrosis and renal function. Design—Native kidney biopsies from 177 patients with chronic renal injury were assessed for interstitial fibrosis, glomerular sclerosis, and GSG+PF. Renal biopsies with active or acute lesions were not included. The percentage of globally sclerotic glomeruli and GSG+PF was correlated with the degree of interstitial fibrosis and serum creatinine levels. Results—The percentage of GSG+PF correlates better with the degree of interstitial fibrosis and renal function than does the percentage of globally sclerotic glomeruli alone. This appears particularly true in chronic renal diseases of patients without diabetes. The number of globally sclerotic glomeruli correlates better with interstitial fibrosis and renal function than does the sum of globally and segmentally sclerotic glomeruli. Conclusions—The percentage of GSG+PF in a renal biopsy specimen provides a better estimate of chronic renal injury than does the percentage of sclerotic glomeruli alone, probably because many or most glomeruli with periglomerular fibrosis are nonfunctional. Therefore, we recommend that the number of glomeruli with periglomerular fibrosis also be provided in the renal biopsy report.

scholarly journals Silencing of long noncoding RNA XIST protects against renal interstitial fibrosis in diabetic nephropathy via microRNA-93-5p-mediated inhibition of CDKN1A

2019 ◽  
Vol 317 (5) ◽  
pp. F1350-F1358 ◽  
Author(s):  
Jindou Yang ◽  
Yan Shen ◽  
Xia Yang ◽  
Yanjun Long ◽  
Shuang Chen ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanism ◽  
High Glucose ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Luciferase Reporter ◽  
Renal Interstitial Fibrosis ◽  
Endogenous Expression

Long noncoding RNAs (lncRNAs) have been reported to play an important role in diabetic nephropathy (DN). However, the molecular mechanism involved in this process remains poorly understood. Thus, the present study aimed to explore the function and molecular mechanism of dysregulated lncRNA X-inactive specific transcript (XIST) in DN. DN mouse models were established by streptozotocin treatment, and human renal tubular epithelial HK-2 cells were exposed to high glucose to produce an in vitro model. XIST was highly expressed in renal tissues of patients with DN, mice with DN, and high glucose-exposed HK-2 cells. To identify the interaction among XIST, miR-93-5p, and cyclin-dependent kinase inhibitor 1A (CDKN1A) and to analyze the functional significance of their interaction in renal interstitial fibrosis, we altered endogenous expression of XIST and miR-93-5p and CDKN1A. Dual-luciferase reporter assay results suggested that XIST was highly expressed in the kidney tissue of DN mice and high glucose-exposed HK-2 cells. XIST was identified to be a lncRNA that could bind to miR-93-5p, and CDKN1A was a target of miR-93-5p. Downregulated expression of XIST led to an increase in miR-93-5p expression, thereby decreasing CDKN1A and suppressing renal interstitial fibrosis in DN. Consistently, XIST knockdown reduced the expression of fibrosis markers (fibronectin, collagen type IV, and transforming growth factor-β1). Restoration of CDKN1A or decreasing miR-93-5p yielded a reversed effect on renal interstitial fibrosis. In conclusion, our study demonstrated that silenced XIST inducing miR-93-5p-dependent CDKN1A inhibition was beneficial for preventing renal interstitial fibrosis in DN, which may provide a future strategy to prevent the progression of DN.

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