The role of endoglin in kidney fibrosis

Renal Fibrosis ◽

Mesangial Cells ◽

Cell Types ◽

Experimental Models ◽

Kidney Fibrosis ◽

End Stage

Tubulointerstitial fibrosis and glomerulosclerosis, are a major feature of end stage chronic kidney disease (CKD), characterised by an excessive accumulation of extracellular matrix (ECM) proteins. Transforming growth factor beta-1 (TGF-β1) is a cytokine with an important role in many steps of renal fibrosis such as myofibroblast activation and proliferation, ECM protein synthesis and inflammatory cell infiltration. Endoglin is a TGF-β co-receptor that modulates TGF-β responses in different cell types. In numerous cells types, such as mesangial cells or myoblasts, endoglin regulates negatively TGF-β-induced ECM protein expression. However, recently it has been demonstrated that ‘in vivo’ endoglin promotes fibrotic responses. Furthermore, several studies have demonstrated an increase of endoglin expression in experimental models of renal fibrosis in the kidney and other tissues. Nevertheless, the role of endoglin in renal fibrosis development is unclear and a question arises: Does endoglin protect against renal fibrosis or promotes its development? The purpose of this review is to critically analyse the recent knowledge relating to endoglin and renal fibrosis. Knowledge of endoglin role in this pathology is necessary to consider endoglin as a possible therapeutic target against renal fibrosis.

Insights into the mechanisms of renal fibrosis: is it possible to achieve regression?

AJP Renal Physiology ◽

10.1152/ajprenal.00453.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. F227-F234 ◽

Cited By ~ 54

Author(s):

Christos Chatziantoniou ◽

Jean-Claude Dussaule

Keyword(s):

Renal Fibrosis ◽

Experimental Models ◽

Future Directions ◽

Vasoactive Peptides ◽

Clinical Considerations ◽

Antihypertensive Treatments ◽

Bone Morphogenic Protein 7

Recent evidence suggests that the progression of renal fibrosis is a reversible process, at least in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. The involved mechanisms are discussed with particular emphasis on the fibrotic role of vasoactive peptides such as angiotensin II and endothelin and growth factors such as transforming growth factor (TGF)-β. The possibility of regression is introduced by presenting the in vivo efficiency of antihypertensive treatments and of systems that antagonize the fibrogenic action of TGF-β such as bone morphogenic protein-7 and HGF. Finally, we provide a brief description of the promising future directions and clinical considerations about the applications of the experimental data to humans.

NQO1 Deficiency Aggravates Renal Injury by Dysregulating Vps34/ATG14L Complex during Autophagy Initiation in Diabetic Nephropathy

Antioxidants ◽

10.3390/antiox10020333 ◽

2021 ◽

Vol 10 (2) ◽

pp. 333

Author(s):

Geum-Lan Hong ◽

Kyung-Hyun Kim ◽

Chul-Ho Lee ◽

Tae-Won Kim ◽

Ju-Young Jung

Keyword(s):

Diabetic Nephropathy ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Cell Damage ◽

End Stage ◽

Hk2 Cells ◽

Tgf Β1

Diabetic nephropathy (DN) is one of the causes of end-stage renal failure, featuring renal fibrosis. However, autophagy, a vital process for intracellular homeostasis, can counteract renal fibrosis. Moreover, NAD(P)H: quinone dehydrogenase 1 (NQO1) modulates the ratios of reduced/oxidized nicotinamide nucleotides, exerting a cytoprotective function. Here, to examine the role of NQO1 genes in DN progression, the levels of autophagy-related proteins and pro-fibrotic markers were assessed in silencing or overexpression of NQO1 in human proximal tubular cells (HK2), and C57BL/6 (wild-type) and Nqo1 knockout (KO) mice injected to streptozotocin (50 mg/kg). NQO1 deficiency impaired the autophagy process by suppressing basal expression of ClassⅢ PI 3-kinase (Vps34) and autophagy-related (ATG)14L and inducing the expressions of transforming growth factor beta (TGF-β1), Smad3, and matrix metallopeptidase9 (MMP9) in high-glucose (HG) -treated HK2 cells. Meanwhile, NQO1 overexpression increased the expression of Vps34 and ATG14L, while, reducing TGF-β1, Smad3 and MMP9 expression. In vivo, the expression of Vps34 and ATG14L were suppressed in Nqo1 KO mice indicating aggravated glomerular changes and interstitial fibrosis. Therefore, NQO1 deficiency dysregulated autophagy initiation in HK2 cells, with consequent worsened renal cell damage under HG condition. Moreover, STZ-treated Nqo1 KO mice showed that NQO1 deficiency aggravated renal fibrosis by dysregulating autophagy.

The Role of the TGF-β Coreceptor Endoglin in Cancer

The Scientific World JOURNAL ◽

10.1100/tsw.2010.230 ◽

2010 ◽

Vol 10 ◽

pp. 2367-2384 ◽

Cited By ~ 64

Author(s):

Eduardo Pérez-Gómez ◽

Gaelle del Castillo ◽

Juan Francisco Santibáñez ◽

Jose Miguel Lêpez-Novoa ◽

Carmelo Bernabéu ◽

...

Keyword(s):

Tumor Development ◽

Experimental Models ◽

Type I ◽

Type Ii ◽

Invasion And Metastasis ◽

Promising Target ◽

Growth Factor Beta

Endoglin (CD105) is an auxiliary membrane receptor of transforming growth factor beta (TGF-β) that interacts with type I and type II TGF-β receptors and modulates TGF-β signaling. Endoglin is overexpressed in the tumor-associated vascular endothelium, where it modulates angiogenesis. This feature makes endoglin a promising target for antiangiogenic cancer therapy. In addition, recent studies on human and experimental models of carcinogenesis point to an important tumor cell–autonomous role of endoglin by regulating proliferation, migration, invasion, and metastasis. These studies suggest that endoglin behaves as a suppressor of malignancy in experimental and human epithelial carcinogenesis, although it can also promote metastasis in other types of cancer. In this review, we evaluate the implication of endoglin in tumor development underlying studies developed in our laboratories in recent years.

Absence of transforming growth factor beta 1 in murine platelets reduces neointima formation without affecting arterial thrombosis

Thrombosis and Haemostasis ◽

10.1160/th17-02-0112 ◽

2017 ◽

Vol 117 (09) ◽

pp. 1782-1797 ◽

Cited By ~ 5

Author(s):

Eva Schütz ◽

Magdalena L. Bochenek ◽

Dennis R. Riehl ◽

Markus Bosmann ◽

Thomas Münzel ◽

...

Keyword(s):

Growth Factor ◽

Smooth Muscle Actin ◽

Arterial Injury ◽

Neointima Formation ◽

Proliferating Cells ◽

The Media

SummaryPlatelet degranulation at the site of vascular injury prevents bleeding and may affect the chronic vascular wound healing response. Transforming Growth Factor (TGF)-β1 is a major component of platelet α-granules known to accumulating in thrombi. It was our aim to determine the role of TGFβ1 released from activated platelets for neointima formation following arterial injury and thrombosis. Mice with platelet-specific deletion of TGFβ1 (Plt.TGFβ-KO) underwent carotid artery injury. Immunoassays confirmed the absence of active TGFβ1 in platelet releasates and plasma of Plt.TGFβ-KO mice. Whole blood analyses revealed similar haematological parameters, and tail cut assays excluded major bleeding defects. Platelet aggregation and the acute thrombotic response to injury in vivo did not differ between Plt.TGFβ-KO and Plt.TGFβ-WT mice. Morphometric analysis revealed that absence of TGFβ1 in platelets resulted in a significant reduction of neointima formation with lower neointima area, intima-to-media ratio, and lumen stenosis. On the other hand, the media area was enlarged in mice lacking TGFβ1 in platelets and contained increased amounts of proteases involved in latent TGFβ activation, including MMP2, MMP9 and thrombin. Significantly increased numbers of proliferating cells and cells expressing the mesenchymal markers platelet-derived growth factor receptor-β or fibroblast-specific protein-1, and the macrophage antigen F4/80, were observed in the media of Plt.TGFβ-KO mice, whereas the medial smooth muscle-actin-immuno-positive area and collagen content did not differ between genotypes. Our findings support an essential role for platelet-derived TGFβ1 for the vascular remodelling response to arterial injury, apparently independent from the role of platelets in thrombosis or haemostasis.Supplementary Material to this article is available online at www.thrombosis-online.com.

Activin A regulates activation of mouse neutrophils by Smad3 signalling

Open Biology ◽

10.1098/rsob.160342 ◽

2017 ◽

Vol 7 (5) ◽

pp. 160342 ◽

Cited By ~ 13

Author(s):

Yan Qi ◽

Jingyan Ge ◽

Chunhui Ma ◽

Na Wu ◽

Xueling Cui ◽

...

Keyword(s):

Activin A ◽

Target Cells ◽

Inflammatory Factor ◽

Important Regulator ◽

Growth Factor Beta ◽

Species Production

Activin A, a member of the transforming growth factor beta superfamily, acts as a pro-inflammatory factor in acute phase response, and influences the pathological progress of neutrophil-mediated disease. However, whether activin A can exert an effect on the activities of neutrophils remains unclear. In this study, we found that the release of activin A was enhanced from neutrophils of mouse when stimulated with lipopolysaccharide. Furthermore, neutrophils were not only the source of activin A but also the target cells in response to activin A, in which canonical activin signalling components existed, and levels of ACTRIIA, SMAD3 and p-SMAD3 proteins were elevated in activin A-treated neutrophils. Next, the role of activin A was determined in regulation of neutrophils activities. Our data revealed that activin A induced O 2 − release and reactive oxygen species production, promoted IL-6 release, and enhanced phagocytosis, but failed to attract neutrophils migrating across the trans-well membrane. Moreover, we found that effect of activin A on IL-6 release from the peritoneal neutrophils of mouse was significantly attenuated by in vivo Smad3 knockdown. In summary, these data demonstrate that activin A can exert an effect on neutrophils activation in an autocrine/paracrine manner through Smad3 signalling, suggesting that activin A is an important regulator of neutrophils.

Smad3 mediates ANG II-induced hypertensive kidney disease in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00595.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. F986-F997 ◽

Cited By ~ 59

Author(s):

Zhen Liu ◽

Xiao R. Huang ◽

Hui Y. Lan

Keyword(s):

Angiotensin Ii ◽

Renal Fibrosis ◽

Monocyte Chemoattractant Protein 1

Mesangial Cells ◽

Type I ◽

Hypertensive Nephropathy ◽

Renal Inflammation ◽

Although Smad3 is a key mediator for fibrosis, its functional role and mechanisms in hypertensive nephropathy remain largely unclear. This was examined in the present study in a mouse model of hypertension induced in Smad3 knockout (KO) and wild-type (WT) mice by subcutaneous angiotensin II infusion and in vitro in mesangial cells lacking Smad3. After angiotensin II infusion, both Smad3 KO and WT mice developed equally high levels of blood pressure. However, disruption of Smad3 prevented angiotensin II-induced kidney injury by lowering albuminuria and serum creatinine ( P < 0.01), inhibiting renal fibrosis such as collagen type I and IV, fibronectin, and α-SMA expression (all P < 0.01), and blocking renal inflammation including macrophage and T cell infiltration and upregulation of IL-1β, TNF-α, and monocyte chemoattractant protein-1 in vivo and in vitro (all P < 0.001). Further studies revealed that blockade of angiotensin II-induced renal transforming growth factor (TGF)-β1 expression and inhibition of Smurf2-mediated degradation of renal Smad7 are mechanisms by which Smad3 KO mice were protected from angiotensin II-induced renal fibrosis and NF-κB-driven renal inflammation in vivo and in vitro. In conclusion, Smad3 is a key mediator of hypertensive nephropathy. Smad3 promotes Smurf2-dependent ubiquitin degradation of renal Smad7, thereby enhancing angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy.

Regulatory Effect of 1,25(OH)2D3 on TGF-β1 and miR-130b Expression in Streptozotocin-Induced Diabetic Nephropathy in Rats

International Journal of Endocrinology ◽

10.1155/2019/1231346 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Yuetong Liu ◽

Ye Yang ◽

Qin Wang ◽

Apaer Kahaer ◽

Jiyun Zhang ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Western Blotting ◽

Renal Fibrosis ◽

Peanut Oil ◽

Kidney Fibrosis ◽

Protein Levels ◽

Hematoxylin And Eosin

Objective. To investigate the role of microRNA-130b in 1,25(OH)2D3 mediated improvement of renal fibrosis via transforming growth factor-beta 1 in a rat model of diabetic nephropathy (DN). Methods. DN was induced in 30 rats by intraperitoneal injection of streptozotocin. These rats were randomly allocated to the DN group, TGF-β1 overexpression group (in situ injection of TGF-β1 lentivirus to kidney tissues), and TGF-β1 siRNA group (in situ injection of TGF-β1 siRNA lentivirus to kidney tissues). Rats with different expression levels of TGF-β1 were administered 1,25(OH)2D3 (0.03 μg/kg/d) or peanut oil as control. DN rats were treated only with peanut oil. All rats were randomly divided into five groups (n = 6 per group): TGF-β1 overexpression + oil, TGF-β1 overexpression + 1,25(OH)2D3, TGF-β1 siRNA + oil, TGF-β1 siRNA + 1,25(OH)2D3, and DN + oil groups. After 37 days, kidney samples were collected and the expression of TGF-β1 and miR-130b was determined by real-time PCR, western blotting, and immunohistochemistry. Hematoxylin and eosin staining and Masson staining were used to evaluate kidney morphological and fibrogenic changes. Differences were determined using ANOVA and Student’s t-test. Results. RT-PCR, western blotting, and immunohistochemistry revealed that interference of TGF-β1 significantly decreased mRNA and protein levels of TGF-β1 in renal tissues of DN rats compared to those in renal tissues of rats overexpressing TGF-β1 (p<0.05). Histological analysis showed that upregulated TGF-β1 led to disorganized kidney structure and severe kidney fibrosis. The expression of miR-130b was significantly lowered upon lentivirus-mediated overexpression of TGF-β1 than upon downregulation of TGF-β1 (p<0.05). Treatment with 1,25(OH)2D3 led to a significant reduction of TGF-β1 at the mRNA and protein levels (both p<0.05), improvement of renal structure and fibrosis, and an increase in miR-130b expression (p<0.05). Conclusion. TGF-β1 can decrease the expression of miR-130b in kidney tissues of DN rats. Moreover, miR-130b may be involved in the protective effect of 1,25(OH)2D3 on renal fibrosis via TGF-β1.

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin

Scientific Reports ◽

10.1038/s41598-020-80199-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Neel Mehta ◽

Renzhong Li ◽

Dan Zhang ◽

Asfia Soomro ◽

Juehua He ◽

...

Keyword(s):

Renal Fibrosis ◽

Mesangial Cells ◽

Matrix Proteins ◽

Membrane Microdomains ◽

Glomerular Mesangial Cells ◽

Wild Type ◽

Caveolin 1 ◽

Inhibition Studies

AbstractCaveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3′UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFβ1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFβ1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFβ1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD.

TAK1 Inhibitor Enhances the Therapeutic Treatment for Glioblastoma

Cancers ◽

10.3390/cancers13010041 ◽

2020 ◽

Vol 13 (1) ◽

pp. 41

Author(s):

Michela Campolo ◽

Marika Lanza ◽

Giovanna Casili ◽

Irene Paterniti ◽

Alessia Filippone ◽

...

Keyword(s):

Cell Lines ◽

Xenograft Model ◽

Tumor Burden ◽

Mitogen Activated Protein Kinase ◽

Therapeutic Treatment

Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direction for treating GBM. Transforming growth factor-beta-activated kinase-1 (TAK1) is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways; however, the role of TAK1 in GBM-chemoresistance remains unknown. This study aimed to verify, in GBM human cell lines, in an in vivo U87-xenograft model and in TMZ-treated-patients, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy. In vitro model, using GBM cell lines, showed that 5Z-7-oxozeaenol augmented the cytotoxic effects of TMZ, blocking TMZ-induced NF-κB-activation, reducing DNA-damage and enhancing TMZ-induced apoptosis in GMB cell lines. We showed a reduction in tumor burden as well as tumor volume in the xenograft model following the treatment with 5Z-7-oxozaenol associated with TMZ. Our results showed a significant up-regulation in TAK1, p-p38, p-JNK and NF-κB in glioblastoma TMZ-treated-patients and denoted the role of 5Z-7-oxozeaenol in increasing the sensitivity of GBM cells to chemotherapy, proving to be an effective coadjuvant to current GBM chemotherapeutic regimens, suggesting a new option for therapeutic treatment of GBM.

New Insights into Cancer Targeted Therapy: Nodal and Cripto-1 as Attractive Candidates

International Journal of Molecular Sciences ◽

10.3390/ijms22157838 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7838

Author(s):

Paola Arboretto ◽

Michele Cillo ◽

Antonio Leonardi

Keyword(s):

Targeted Therapy ◽

Cancer Cells ◽

Differentiated Cells ◽

Medical Need ◽

Cancer Targeted Therapy

The transforming growth factor beta (TGF-β) signaling is fundamental for correct embryonic development. However, alterations of this pathway have been correlated with oncogenesis, tumor progression and sustaining of cancer stem cells (CSCs). Cripto-1 (CR-1) and Nodal are two embryonic proteins involved in TGF-β signaling. Their expression is almost undetectable in terminally differentiated cells, but they are often re-expressed in tumor cells, especially in CSCs. Moreover, cancer cells that show high levels of CR-1 and/or Nodal display more aggressive phenotypes in vitro, while in vivo their expression correlates with a worse prognosis in several human cancers. The ability to target CSCs still represents an unmet medical need for the complete eradication of certain types of tumors. Given the prognostic role and the selective expression of CR-1 and Nodal on cancer cells, they represent archetypes for targeted therapy. The aim of this review is to clarify the role of CR-1 and Nodal in cancer stem populations and to summarize the current therapeutic strategy to target CSCs using monoclonal antibodies (mAbs) or other molecular tools to interfere with these two proteins.