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.

MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway

2018 ◽  
Vol 132 (21) ◽  
pp. 2339-2355 ◽  
Author(s):  
Zhenzhen Li ◽  
Xianghua Liu ◽  
Fengyan Tian ◽  
Ji Li ◽  
Qingwei Wang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Signaling ◽  
Mesenchymal Transition ◽  
Amino Terminal ◽  
Ureter Obstruction ◽  
Tgf Β1

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-β1 (TGF-β1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-β1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-β1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-β1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-β1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-β1, and MKP2 overexpression inhibits TGF-β1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

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.

scholarly journals Long Noncoding RNA Tug1 Promotes Angiotensin II–Induced Renal Fibrosis by Binding to Mineralocorticoid Receptor and Negatively Regulating MicroR-29b-3p

Hypertension ◽  
2021 ◽  
Author(s):  
Juhong Zhang ◽  
Yuqing Zhang ◽  
Jing Gao ◽  
Meihui Wang ◽  
Xiaoting Li ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Real Time ◽  
Long Noncoding Rna ◽  
Mineralocorticoid Receptor ◽  
Renal Fibrosis ◽  
Noncoding Rna ◽  
Epithelial To Mesenchymal Transition ◽  
Chain Reaction ◽  
Mesenchymal Transition ◽  
Polymerase Chain

Inappropriately activation of renin-angiotensin-aldosterone system induced renal fibrosis is characterized by partial epithelial-to-mesenchymal transition. Previously, we have indicated that miR-29b-3p in inhibiting partial epithelial-to-mesenchymal transition by negatively regulating extracellular matrix gene expression in the kidney. Despite the critical role of miR-29b-3p in fibrosis, the molecular mechanisms by which miR-29b-3p is regulated under the condition of profibrotic stimuli are largely unknown. Our aim is to search for the long noncoding RNA that mediated sponge regulatory on miR-29b-3p, and whether the long noncoding RNA could be activated by renin-angiotensin-aldosterone system and its consequent effects on renal fibrosis. Bioinformatics analysis predicted that Tug1 might directly bound to miR-29b-3p and function as a competing endogenous RNA. Dual-luciferase reporter assay, fluorescence in situ hybridization, and real-time polymerase chain reaction were performed to indicate that Tug1 interact with miR-29b-3p in a sequence-specific manner. Decreased Tug1 led to an increase in extracellular matrix measured by Western blot, and this effect was enhanced by miR-29b-3p measured by real-time polymerase chain reaction and Western blot, suggesting cross-regulation between the RNAs. Bioinformatics analysis predicted that mineralocorticoid receptor might bind to long noncoding RNA Tug1 . Notably, mineralocorticoid receptor antagonism reduced Tug1 expression in the presence or absence of angiotensin II or aldosterone measured by real-time polymerase chain reaction, and RNA immunoprecipitation assays confirmed that the mineralocorticoid receptor directly bound to Tug1 . Finally, we confirmed that Tug1 expression was enhanced in fibrotic compared with nonfibrotic human renal biopsy samples using RNA-in situ hybridization. Our findings provide novel insights into the molecular mechanism of Ang II–induced renal fibrosis and identify the Tug1 –miR-29b-3p axis as an important target of MR activation.

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.

Loss of vitamin D receptor in chronic kidney disease: a potential mechanism linking inflammation to epithelial-to-mesenchymal transition

2012 ◽  
Vol 303 (7) ◽  
pp. F1107-F1115 ◽  
Author(s):  
Min Xiong ◽  
Junbo Gong ◽  
Youhua Liu ◽  
Rong Xiang ◽  
Xiaoyue Tan
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Kidney Diseases ◽  
Ectopic Expression ◽  
Mesenchymal Transition ◽  
Tnf Α ◽  
Tgf Β1

Both peritubular inflammation and tubular epithelial-to-mesenchymal transition (EMT) are critical events during the pathogenesis of renal fibrosis. However, the relationship between these two processes is unclear. Here, we investigated the potential role of the vitamin D receptor (VDR) in coupling peritubular inflammation and EMT. In a mouse model of unilateral ureteral obstruction (UUO), loss of VDR was observed as early as 1 day after surgery. In cultured proximal tubular epithelial HK-2 cells, proinflammatory TNF-α inhibited the expression of VDR in a dose- and time-dependant manner. Treatment with TNF-α sensitized HK-2 cells to EMT stimulated by transforming growth factor (TGF)-β1. Ectopic expression of VDR counteracted the synergistic effect of TNF-α and TGF-β1 on EMT. Furthermore, knockdown of VDR using a small interfering RNA strategy mimicked the effect of TNF-α on facilitating EMT. Either TNF-α treatment or a loss of VDR induced β-catenin activation and its nuclear translocation. The VDR ligand calcitriol reversed the VDR loss and inhibited EMT in the mouse UUO model, and late administration of active vitamin D was effective in restoring VDR expression as well, and reduced collagen accumulation and deposition compared with the vehicle control. β-Catenin expression induced by UUO was also significantly inhibited after the late administration of vitamin D. These results indicate that the early loss of VDR in chronic kidney diseases was likely mediated by proinflammatory TNF-α, which renders tubular cells susceptible to EMT. Our data suggest that loss of VDR couples peritubular inflammation and EMT, two key events in renal fibrogenesis.

scholarly journals Metformin Improves Epithelial-to-Mesenchymal Transition Induced by TGF-β1 in Renal Tubular Epithelial NRK-52E Cells via Inhibiting Egr-1

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Meiping Guan ◽  
Wenqi Li ◽  
Lingling Xu ◽  
Yanmei Zeng ◽  
Dan Wang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mesenchymal Transition ◽  
Early Growth Response ◽  
Real Time Quantitative Pcr ◽  
Novel Target ◽  
Renal Tubular ◽  
Tgf Β1 ◽  
E Cadherin

The early growth response- (Egr-) 1 has been found to play a key role in organ fibrosis. Metformin has been shown to be effective in attenuating renal tubular epithelial-to-mesenchymal transition (EMT), which is involved in renal fibrosis. However, it is unknown whether metformin improves EMT via inhibiting Egr-1. In this study, rat renal tubular epithelial (NRK-52 E) cells, treated by transforming growth factor- (TGF-)β1 of 10 ng/ml with or without metformin of 1 mmol/l, were transfected by siEgr-1 or M61-Egr-1 plasmids to knock down or overexpress Egr-1, respectively. The gene and protein expressions of E-cadherin,α-SMA, fibronectin (FN), and Egr-1 were determined by real-time quantitative PCR and Western blotting, respectively. We observed that TGF-β1 significantly reduced E-cadherin expression and upregulated the expressions of FN,α-SMA, and Egr-1, which can be reversed by metformin. M61-Egr-1 transfection could exacerbate EMT, which can be reversed by metformin. Taken together, our data show that Egr-1 plays an important role in TGF-β1-induced EMT of renal tubular epithelial cells and metformin improves EMT while inhibiting Egr-1, which provides a potential novel target to combat renal fibrosis.

scholarly journals Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD

2018 ◽  
Vol 50 (1) ◽  
pp. 20-34 ◽  
Author(s):  
Wenshan Lv ◽  
Fan Fan ◽  
Yangang Wang ◽  
Ezekiel Gonzalez-Fernandez ◽  
Chen Wang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Noncoding Rna ◽  
Therapeutic Potential ◽  
Public Health Issue ◽  
Rna Molecules ◽  
Small Noncoding Rna ◽  
Cellular Processes ◽  
Initial Injury ◽  
Stage Renal Disease ◽  
End Stage

Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, is increasingly becoming a major public health issue. At the histological level, renal fibrosis is the final common pathway leading to end-stage renal disease, irrespective of the initial injury. According to this view, antifibrotic agents should slow or halt the progression of CKD. However, due to multiple overlapping pathways stimulating fibrosis, it has been difficult to develop antifibrotic drugs that delay or reverse the progression of CKD. MicroRNAs (miRNAs) are small noncoding RNA molecules, 18–22 nucleotides in length, that control many developmental and cellular processes as posttranscriptional regulators of gene expression. Emerging evidence suggests that miRNAs targeted against genes involved in renal fibrosis might be potential candidates for the development of antifibrotic therapies for CKD. This review will discuss some of the miRNAs, such as Let-7, miR-21,-29, -192, -200,-324, -132, -212, -30, -126, -433, -214, and -199a, that are implicated in renal fibrosis and the potential to exploit these molecular targets for the treatment of CKD.

Long noncoding RNAlnc-TSIinhibits renal fibrogenesis by negatively regulating the TGF-β/Smad3 pathway

2018 ◽  
Vol 10 (462) ◽  
pp. eaat2039 ◽  
Author(s):  
Peng Wang ◽  
Man-Li Luo ◽  
Erwei Song ◽  
Zhanmei Zhou ◽  
Tongtong Ma ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Renal Fibrosis ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β ◽  
Smad3 Phosphorylation ◽  
Β Receptor ◽  
Almost All ◽  
Renal Fibrogenesis

Transforming growth factor–β (TGF-β) is a well-established central mediator of renal fibrosis, a common outcome of almost all progressive chronic kidney diseases. Here, we identified a poorly conserved and kidney-enriched long noncoding RNA in TGF-β1–stimulated human tubular epithelial cells and fibrotic kidneys, which we termed TGF-β/Smad3-interacting long noncoding RNA (lnc-TSI).Lnc-TSIwas transcriptionally regulated by Smad3 and specifically inhibited TGF-β–induced Smad3 phosphorylation and downstream profibrotic gene expression.Lnc-TSIacted by binding with the MH2 domain of Smad3, blocking the interaction of Smad3 with TGF-β receptor I independent of Smad7. Delivery of humanlnc-TSIinto unilateral ureteral obstruction (UUO) mice, a well-established model of renal fibrosis, inhibited phosphorylation of Smad3 in the kidney and attenuated renal fibrosis. In a cohort of 58 patients with biopsy-confirmed IgA nephropathy (IgAN),lnc-TSIrenal expression negatively correlated with the renal fibrosis index (r= −0.56,P< 0.001) after adjusting for cofounders. In a longitudinal study, 32 IgAN patients with low expression of renallnc-TSIat initial biopsy had more pronounced increases in their renal fibrosis index and experienced stronger declines in renal function at repeat biopsy at a mean of 48 months of follow-up. These data suggest thatlnc-TSIreduced renal fibrogenesis through negative regulation of the TGF-β/Smad pathway.

scholarly journals Role of microRNAs in Obesity-Related Kidney Disease

2021 ◽  
Vol 22 (21) ◽  
pp. 11416
Author(s):  
Maite Caus ◽  
Àuria Eritja ◽  
Milica Bozic
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Significant Risk ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Rna Molecules ◽  
Small Noncoding Rna ◽  
Post Transcriptional Regulation

Obesity is a major global health problem and is associated with a significant risk of renal function decline. Obesity-related nephropathy, as one of the complications of obesity, is characterized by a structural and functional damage of the kidney and represents one of the important contributors to the morbidity and mortality worldwide. Despite increasing data linking hyperlipidemia and lipotoxicity to kidney injury, the apprehension of molecular mechanisms leading to a development of kidney damage is scarce. MicroRNAs (miRNAs) are endogenously produced small noncoding RNA molecules with an important function in post-transcriptional regulation of gene expression. miRNAs have been demonstrated to be important regulators of a vast array of physiological and pathological processes in many organs, kidney being one of them. In this review, we present an overview of miRNAs, focusing on their functional role in the pathogenesis of obesity-associated renal pathologies. We explain novel findings regarding miRNA-mediated signaling in obesity-related nephropathies and highlight advantages and future perspectives of the therapeutic application of miRNAs in renal diseases.

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