Role of the TGF-β/BMP-7/Smad pathways in renal diseases

2012 ◽  
Vol 124 (4) ◽  
pp. 243-254 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Arthur C. K. Chung ◽  
Hui Y. Lan
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Biological Activities ◽  
Transforming Growth Factor Β ◽  
Renal Diseases ◽  
Ubiquitin E3 Ligase ◽  
Tgf Β1

TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, a ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signalling and has therapeutic effect on CKDs. Recent studies also found that Smad3 mediated renal fibrosis by up-regulating miR-21 (where miR represents microRNA) and miR-192, but down-regulating miR-29 and miR-200 families. Therefore restoring miR-29/miR-200 or suppressing miR-21/miR-192 is able to treat progressive renal fibrosis. Furthermore, activation of TGF-β/Smad signalling inhibits renal BMP-7 expression and BMP/Smad signalling. On the other hand, overexpression of renal BMP-7 is capable of inhibiting TGF-β/Smad3 signalling and protects the kidney from TGF-β-mediated renal injury. This counter-regulation not only expands our understanding of the causes of renal injury, but also suggests the therapeutic potential by targeting TGF-β/Smad signalling or restoring BMP-7 in CKDs. Taken together, the current understanding of the distinct roles and mechanisms of TGF-β and BMP-7 in CKDs implies that targeting the TGF-β/Smad pathway or restoring BMP-7 signalling may represent novel and effective therapies for CKDs.

Apigenin Alleviates Renal Fibroblast Activation through AMPK and ERK Signaling Pathways In Vitro

2020 ◽  
Vol 21 (11) ◽  
pp. 1107-1118
Author(s):  
Ningning Li ◽  
Zhan Wang ◽  
Tao Sun ◽  
Yanfei Lei ◽  
Xianghua Liu ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Protective Role ◽  
Fibroblast Proliferation ◽  
Fibroblast Activation ◽  
And Function ◽  
Activated Fibroblasts ◽  
Tgf Β1

Objective: Renal fibrosis is a common pathway leading to the progression of chronic kidney disease. Activated fibroblasts contribute remarkably to the development of renal fibrosis. Although apigenin has been demonstrated to play a protective role from fibrotic diseases, its pharmacological effect on renal fibroblast activation remains largely unknown. Materials and Methods: Here, we examined the functional role of apigenin in the activation of renal fibroblasts response to transforming growth factor (TGF)-β1 and its potential mechanisms. Cultured renal fibroblasts (NRK-49F) were exposed to apigenin (1, 5, 10 and 20 μM), followed by the stimulation of TGF-β1 (2 ng/mL) for 24 h. The markers of fibroblast activation were determined. In order to confirm the anti-fibrosis effect of apigenin, the expression of fibrosis-associated genes in renal fibroblasts was assessed. As a consequence, apigenin alleviated fibroblast proliferation and fibroblastmyofibroblast differentiation induced by TGF-β1. Result: Notably, apigenin significantly inhibited the fibrosis-associated genes expression in renal fibroblasts. Moreover, apigenin treatment significantly increased the phosphorylation of AMP-activated protein kinase (AMPK). Apigenin treatment also obviously reduced TGF-β1 induced phosphorylation of ERK1/2 but not Smad2/3, p38 and JNK MAPK in renal fibroblasts. Conclusion: In a summary, these results indicate that apigenin inhibits renal fibroblast proliferation, differentiation and function by AMPK activation and reduced ERK1/2 phosphorylation, suggesting it could be an attractive therapeutic potential for the treatment of renal fibrosis.

Soluble betaglycan reduces renal damage progression in db/db mice

2007 ◽  
Vol 292 (1) ◽  
pp. F321-F329 ◽  
Author(s):  
Patricia Juárez ◽  
M. Magdalena Vilchis-Landeros ◽  
José Ponce-Coria ◽  
Valentín Mendoza ◽  
Rogelio Hernández-Pando ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Renal Damage ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β ◽  
Collagen Iv ◽  
Term Treatment ◽  
Renal Diseases ◽  
Type I ◽  
Long Term Treatment

Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of renal diseases. Betaglycan, also known as the type III TGF-β receptor, regulates TGF-β action by modulating its access to the type I and II receptors. Betaglycan potentiates TGF-β; however, soluble betaglycan, which is produced by the shedding of the membrane-bound receptor, is a potent antagonist of TGF-β. In the present work, we have used a recombinant form of soluble betaglycan (SBG) to prevent renal damage in genetically obese and diabetic db/db mice. Eight-wk-old db/db or nondiabetic ( db/m) mice were injected intraperitoneally with 50 μg of SBG or vehicle alone three times a wk for 8 wk. The db/db mice that received vehicle presented albuminuria and increased serum creatinine, as well as glomerular mesangial matrix expansion. The db/db mice treated with SBG exhibited a reduction in serum creatinine, albuminuria, and structural renal damage. These effects were associated with lower kidney levels of mRNAs encoding TGF-β1, TGF-β2, TGF-β3, collagen IV, collagen I, fibronectin, and serum glucocorticoid kinase as well as a reduction in the immunostaining of collagen IV and fibronectin. Our data indicate that SBG is a renoprotective agent that neutralized TGF-β actions in this model of nephropathy. Because SBG has a high affinity for all TGF-β isoforms, in particular TGF-β2, it is found naturally in serum and tissues and its shedding may be regulated. We believe that SBG shall prove convenient for long-term treatment of kidney diseases and other pathologies in which TGF-β plays a pathophysiological role.

scholarly journals Targeting TGF-β Signaling in Kidney Fibrosis

2018 ◽  
Vol 19 (9) ◽  
pp. 2532 ◽  
Author(s):  
Yoshitaka Isaka
Keyword(s):  
Intracellular Signaling ◽  
Renal Fibrosis ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β ◽  
Cell Interaction ◽  
Common Pathway ◽  
Kidney Fibrosis ◽  
Fibrotic Diseases

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis.

scholarly journals A Case of Transforming Growth Factor-β-Induced Gene-Related Oculorenal Syndrome: Granular Corneal Dystrophy Type II with a Unique Nephropathy

2016 ◽  
Vol 6 (3) ◽  
pp. 106-113 ◽  
Author(s):  
Yoichi Iwafuchi ◽  
Tetsuo Morioka ◽  
Yuko Oyama ◽  
Kandai Nozu ◽  
Kazumoto Iijima ◽  
...  
Keyword(s):  
Growth Factor ◽  
Basement Membrane ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Renal Involvement ◽  
Transforming Growth Factor Β ◽  
Corneal Dystrophy ◽  
Renal Diseases ◽  
Type Ii ◽  
Granular Corneal Dystrophy

Many types of inherited renal diseases have ocular features that occasionally support a diagnosis. The following study describes an unusual example of a 40-year-old woman with granular corneal dystrophy type II complicated by renal involvement. These two conditions may coincidentally coexist; however, there are some reports that demonstrate an association between renal involvement and granular corneal dystrophy type II. Granular corneal dystrophy type II is caused by a mutation in the transforming growth factor-β-induced (TGFBI) gene. The patient was referred to us because of the presence of mild proteinuria without hematuria that was subsequently suggested to be granular corneal dystrophy type II. A kidney biopsy revealed various glomerular and tubular basement membrane changes and widening of the subendothelial space of the glomerular basement membrane by electron microscopy. However, next-generation sequencing revealed that she had no mutation in a gene that is known to be associated with monogenic kidney diseases. Conversely, real-time polymerase chain reaction, using a simple buccal swab, revealed TGFBI heteromutation (R124H). The TGFBI protein plays an important role in cell-collagen signaling interactions, including extracellular matrix proteins which compose the renal basement membrane. This mutation can present not only as corneal dystrophy but also as renal disease. TGFBI-related oculorenal syndrome may have been unrecognized. It is difficult to diagnose this condition without renal electron microscopic studies. To the best of our knowledge, this is the first detailed report of nephropathy associated with a TGFBI mutation.

scholarly journals Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3068 ◽  
Author(s):  
Wen-Chun Yu ◽  
Ren-Yeong Huang ◽  
Tz-Chong Chou
Keyword(s):  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
High Mobility ◽  
Renal Diseases ◽  
Heme Oxygenase 1 ◽  
Diabetic Mice ◽  
Tgf Β1

Fucoidan extracted from brown algae has multiple beneficial functions. In this study, we investigated the effects of low-molecular-weight fucoidan (oligo-FO) on renal fibrosis under in vitro and in vivo diabetic conditions, and its molecular mechanisms. Advanced glycation product (AGE)-stimulated rat renal proximal tubular epithelial cells (NRK-52E) and diabetic mice induced by high-fat diet and intraperitoneal injection of streptozotocin and nicotinamide were used. Oligo-FO treatment significantly inhibited anti-high mobility group box 1 (HMGB1)/RAGE/ anti-nuclear factor-kappa B (NF-κB)/transforming growth factor-β1 (TGF-β1)/TGF-β1R/Smad 2/3/fibronectin signaling pathway and HIF-1α activation in AGE-stimulated NRK-52E cells. Conversely, the expression and activity of Sirt-1; the levels of ubiquitin-specific peptidase 22 (USP22), p-AMPK, glucagon-like peptide-1 receptor (GLP-1R), and heme oxygenase-1 (HO-1); and Nrf2 activation were remarkably increased by oligo-FO in AGE-stimulated cells. However, the above effects of oligo-FO were greatly diminished by inhibiting Sirt-1, HO-1, or GLP-1R activity. Similar changes of these pro-fibrotic genes in the kidney and a marked attenuation of renal injury and dysfunction were observed in oligo-FO-treated diabetic mice. These findings indicated that the inhibitory effects of the oligo-FO on diabetes-evoked renal fibrosis are mediated by suppressing TGF-β1-activated pro-fibrogenic processes via Sirt-1, HO-1, and GLP-1R dependence. Collectively, fucoidan-containing foods or supplements may be potential agents for ameliorating renal diseases due to excessive fibrosis.

scholarly journals Heightened Crescentic Glomerulonephritis in Immune Challenged 129sv Mice Is TGF-β/Smad3 Dependent

2021 ◽  
Vol 22 (4) ◽  
pp. 2059
Author(s):  
Yong Du ◽  
Chun Xie ◽  
Sneha Ravikumar ◽  
Jacob Orme ◽  
Li Li ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Crescentic Glomerulonephritis ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Serum Levels ◽  
Mrna Levels ◽  
Immune Mediated ◽  
Tgf Β1

The 129sv mouse strain is particularly sensitive to experimental immune-mediated nephritis. Previous studies have indicated that transforming growth factor-β (TGF-β) plays a critical role in both immune modulation and tissue fibrogenesis in various diseases and that its biological activities are exerted via the SMAD family. In this study, we aimed to determine whether TGF-β/SMAD signaling is essential for the development of immune-mediated nephritis in 129sv mice. Relative to C57BL/6J control mice with anti-glomeruli basement membrane (GBM) nephritis, 129sv mice with anti-GBM nephritis exhibited increased renal collagen deposition. Additionally, higher mRNA levels of pro-collagen and collagen IV, higher serum levels of active and total TGF-β1, and increased TGF-β1, TGF-βIIR, and phosphorylated SMAD expression were detected in these mice. Deletion of Smad3 in 129sv mice ameliorated anti-GBM induced nephritis, including crescentic glomerulonephritis. Collectively, these findings indicate that the heightened experimental nephritis and fibrotic disease in the 129sv strain of mice are regulated by SMAD3, which could be a potential therapeutic target for immune-mediated nephritis.

scholarly journals TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Agnieszka Loboda ◽  
Mateusz Sobczak ◽  
Alicja Jozkowicz ◽  
Jozef Dulak
Keyword(s):  
Renal Fibrosis ◽  
Noncoding Rna ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Kidney Diseases ◽  
Renal Diseases ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Small Noncoding Rna

Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.

MKP2 suppresses TGF-β1-induced epithelial-to-mesenchymal transition through JNK inhibition

2019 ◽  
Vol 133 (3) ◽  
pp. 545-550 ◽  
Author(s):  
Ivonne Loeffler
Keyword(s):  
Protein Kinase ◽  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Renal Diseases ◽  
Line System ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
Tgf Β1

Abstract Interstitial fibrosis is a typical feature of end-stage renal diseases, regardless of the initial cause of kidney injury. Epithelial-to-mesenchymal transition (EMT) is a mechanism that is thought to play a role in generating the interstitial matrix-producing myofibroblasts and is prominently induced by the transforming growth factor-β 1 (TGF-β1). TGF-β1 signals through a variety of Smad and non-Smad signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways. In a study published in a recent issue of Clinical Science (Clin. Sci. (2018) 132(21),2339–2355), Li et al. investigated the potential role of the Mitogen-activated protein kinase phosphatase 2 (MKP2), also known as Dusp4, in the control of EMT and renal fibrosis. Based on results obtained with an animal model of kidney fibrosis and a proximal tubular epithelial cell line system, the authors put forward a role for MKP2 as a negative feedback regulator of TGF-β1-induced EMT and fibrosis in the kidney. Intriguingly, MKP2 is found to down-regulate activity of c-Jun, but not that of other MAPKs, extracellular signal-regulated kinases or p38, implying a role for c-Jun N-terminal kinase-dependent signaling in renal fibrosis. In this commentary, I discuss the findings of Li and co-workers in the context of the recent literature placing a focus on potential clinical/therapeutic implications.

scholarly journals Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue-Yu Gu ◽  
Jing-Yun Dou ◽  
Xiao-Ru Huang ◽  
Xu-Sheng Liu ◽  
Hui-Yao Lan
Keyword(s):  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Therapeutic Targets ◽  
Transforming Growth Factor Β ◽  
Renal Inflammation ◽  
Rna Transcripts ◽  
Non Coding Rna ◽  
Potential Applications

Renal fibrosis is one of the most characterized pathological features in chronic kidney disease (CKD). Progressive fibrosis eventually leads to renal failure, leaving dialysis or allograft transplantation the only clinical option for CKD patients. Transforming growth factor-β (TGF-β) is the key mediator in renal fibrosis and is an essential regulator for renal inflammation. Therefore, the general blockade of the pro-fibrotic TGF-β may reduce fibrosis but may risk promoting renal inflammation and other side effects due to the diverse role of TGF-β in kidney diseases. Long non-coding RNAs (lncRNAs) are RNA transcripts with more than 200 nucleotides and have been regarded as promising therapeutic targets for many diseases. This review focuses on the importance of TGF-β and lncRNAs in renal inflammation, fibrogenesis, and the potential applications of TGF-β and lncRNAs as the therapeutic targets and biomarkers in renal fibrosis and CKD are highlighted.

scholarly journals Regulation of Renal Fibrosis by Macrophage Polarization

2015 ◽  
Vol 35 (3) ◽  
pp. 1062-1069 ◽  
Author(s):  
Bixia Pan ◽  
Guohui Liu ◽  
Zongpei Jiang ◽  
Dongwen Zheng
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Background/Aims: Since renal fibrosis always predisposes end-stage renal disease, elucidation of the molecular mechanisms that underlie the progression of renal fibrosis may substantially improve the understanding and treatment for renal failure. Previous studies have highlighted an important counteraction between transforming growth factor β 1 (TGFβ1) and bone morphogenic protein 7 (BMP7) in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells during chronic renal injury. Macrophages are also believed to play a critical role in renal fibrosis. However, the relationship between macrophages and EMT is unknown. Methods: Here, we used a mouse unilateral ureteral obstruction (UUO) model to address to these questions, and analyzed macrophage and its subpopulations purified by flow cytometry. Results: We found that the recruited macrophages are polarized to a M2 subtype after renal injury. M2 macrophages released high levels TGFβ1 to suppress BMP7 to enhance EMT-induced renal fibrosis. Depletion of M2 macrophages, but not of M1 macrophages, specifically inhibited EMT, and subsequently the renal fibrosis. Adoptive transplantation of M2 macrophages deteriorated renal fibrosis. Conclusion: Thus, our study highlights M2 macrophages as a critical target for treating renal fibrosis.

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