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The role of endoglin in kidney fibrosis

Published online by Cambridge University Press:  02 December 2014

Jose M. Muñoz-Felix ,
Barbara Oujo  and
Jose M. Lopez-Novoa
Jose M. Muñoz-Felix
Affiliation:
Renal and Cardiovascular Pathophysiology Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain Institute Queen Sophie for Renal Research (IRSIN, FRIAT), Madrid, Spain
Barbara Oujo
Affiliation:
Renal and Cardiovascular Pathophysiology Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain Institute Queen Sophie for Renal Research (IRSIN, FRIAT), Madrid, Spain
Jose M. Lopez-Novoa*
Affiliation:
Renal and Cardiovascular Pathophysiology Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain Institute Queen Sophie for Renal Research (IRSIN, FRIAT), Madrid, Spain
*
*Corresponding author: Jose M. Lopez-Novoa, Department of Physiology and Pharmacology, University of Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain. E-mail: [email protected]
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Abstract

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.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e18
Copyright
Copyright © Cambridge University Press 2014 

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References

1Remuzzi, A. et al. (2009) Regression of diabetic complications by islet transplantation in the rat. Diabetologia 52, 2653-2661CrossRefGoogle ScholarPubMed
2Boor, P. and Floege, J. (2012) The renal (myo-)fibroblast: a heterogeneous group of cells. Nephrology Dialysis Transplantation 27, 3027-3036CrossRefGoogle ScholarPubMed
3Anand, S., Bitton, A. and Gaziano, T. (2013) The gap between estimated incidence of end-stage renal disease and use of therapy. PLoS ONE 8, e72860CrossRefGoogle Scholar
4Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International 3 (Suppl), 1-150Google Scholar
5Turin, T.C. et al. (2012) Lifetime risk of ESRD. Journal of the American Society of Nephrology 23, 1569-1578CrossRefGoogle ScholarPubMed
6Obrador, G.T., Pereira, B.J. and Kausz, A.T. (2002) Chronic kidney disease in the United States: an underrecognized problem. Seminars in Nephrology 22, 441-448CrossRefGoogle ScholarPubMed
7Hewitson, T.D. (2009) Renal tubulointerstitial fibrosis: common but never simple. American Journal of Physiology – Renal Physiology 296, F1239-F1244CrossRefGoogle ScholarPubMed
8Lopez-Novoa, J.M. et al. (2011) Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications. Journal of Translational Medicine 9, 13CrossRefGoogle ScholarPubMed
9Grande, M.T. and Lopez-Novoa, J.M. (2009) Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nature Reviews Nephrology 5, 319-328CrossRefGoogle ScholarPubMed
10Border, W.A. and Noble, N.A. (1997) TGF-beta in kidney fibrosis: a target for gene therapy. Kidney International 51, 1388-1396CrossRefGoogle ScholarPubMed
11Wang, W., Koka, V. and Lan, H.Y. (2005) Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology (Carlton) 10, 48-56CrossRefGoogle ScholarPubMed
12Lopez-Hernandez, F.J. and Lopez-Novoa, J.M. (2012) Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell and Tissue Research 347, 141-154CrossRefGoogle ScholarPubMed
13Yamamoto, T. et al. (1999) Increased levels of transforming growth factor-beta in HIV-associated nephropathy. Kidney International 55, 579-592CrossRefGoogle ScholarPubMed
14Yamamoto, T. et al. (1996) Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney International 49, 461-469CrossRefGoogle ScholarPubMed
15Meyer, A. et al. (2012) Platelet TGF-beta1 contributions to plasma TGF-beta1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood 119, 1064-1074CrossRefGoogle Scholar
16Pimentel, J.L. Jr et al. (1995) Role of angiotensin II in the expression and regulation of transforming growth factor-beta in obstructive nephropathy. Kidney International 48, 1233-1246CrossRefGoogle ScholarPubMed
17Rodriguez-Pena, A. et al. (2002) Endoglin upregulation during experimental renal interstitial fibrosis in mice. Hypertension 40, 713-720CrossRefGoogle ScholarPubMed
18Peters, H., Border, W.A. and Noble, N.A. (1998) Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade. Kidney International 54, 1570-1580CrossRefGoogle ScholarPubMed
19Ding, Y. et al. (2014) Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. Journal of the American Society of Nephrology.CrossRefGoogle ScholarPubMed
20Nogare, A.L. et al. (2013) Expression of fibrosis-related genes in human renal allografts with interstitial fibrosis and tubular atrophy. Journal of Nephrology 26, 1179-1187CrossRefGoogle ScholarPubMed
21Lim, B.J. et al. (2009) Expression of fibrosis-associated molecules in IgA nephropathy treated with cyclosporine. Pediatric Nephrology 24, 513-519CrossRefGoogle ScholarPubMed
22Yamamoto, T. et al. (1993) Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proceedings of the National Academy of Sciences of the United States of America 90, 1814-1818CrossRefGoogle ScholarPubMed
23Sutaria, P.M. et al. (1998) Transforming growth factor-beta receptor types I and II are expressed in renal tubules and are increased after chronic unilateral ureteral obstruction. Life Sciences 62, 1965-1972CrossRefGoogle ScholarPubMed
24Cohen, M.P. et al. (1998) The renal TGF-beta system in the db/db mouse model of diabetic nephropathy. Experimental Nephrology 6, 226-233CrossRefGoogle ScholarPubMed
25Prieto, M. et al. (2005) Temporal changes in renal endoglin and TGF-beta1 expression following ureteral obstruction in rats. Journal of Physiology and Biochemistry 61, 457-467CrossRefGoogle ScholarPubMed
26Meng, X.M., Chung, A.C. and Lan, H.Y. (2013) Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clinical Science (London) 124, 243-254CrossRefGoogle ScholarPubMed
27Munoz-Felix, J.M., Gonzalez-Nunez, M. and Lopez-Novoa, J.M. (2013) ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? Cytokine and Growth Factor Reviews 24, 523-537CrossRefGoogle ScholarPubMed
28Loeffler, I. and Wolf, G. (2014) Transforming growth factor-beta and the progression of renal disease. Nephrology Dialysis Transplantation 29 (Suppl 1), i37-i45CrossRefGoogle ScholarPubMed
29Garcia-Sanchez, O., Lopez-Hernandez, F.J. and Lopez-Novoa, J.M. (2010) An integrative view on the role of TGF-beta in the progressive tubular deletion associated with chronic kidney disease. Kidney International 77, 950-955CrossRefGoogle ScholarPubMed
30Lan, H.Y. (2011) Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. International Journal of Biological Sciences 7, 1056-1067CrossRefGoogle ScholarPubMed
31Kopp, J.B. et al. (1996) Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Laboratory Investigation 74, 991-1003Google ScholarPubMed
32Terrell, T.G. et al. (1993) Pathology of recombinant human transforming growth factor-beta 1 in rats and rabbits. International Review of Experimental Pathology 34 (Pt B), 43-67CrossRefGoogle ScholarPubMed
33Ledbetter, S. et al. (2000) Renal fibrosis in mice treated with human recombinant transforming growth factor-beta2. Kidney International 58, 2367-2376CrossRefGoogle ScholarPubMed
34Zoja, C. et al. (1997) The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are solely due to the inhibition of angiotensin II: evidence based on comparative studies with a receptor antagonist. American Journal of Kidney Diseases 29, 254-264CrossRefGoogle Scholar
35Ziyadeh, F.N. (2004) Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. Journal of American Society of Nephrology 15 (Suppl 1), S55-S57CrossRefGoogle ScholarPubMed
36Miyajima, A. et al. (2000) Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney International 58, 2301-2313CrossRefGoogle ScholarPubMed
37Ma, L.J. et al. (2004) Divergent effects of low versus high dose anti-TGF-beta antibody in puromycin aminonucleoside nephropathy in rats. Kidney International 65, 106-115CrossRefGoogle ScholarPubMed
38Meulmeester, E. and Ten Dijke, P. (2011) The dynamic roles of TGF-beta in cancer. Journal of Pathology 223, 205-218CrossRefGoogle ScholarPubMed
39ten Dijke, P. and Hill, C.S. (2004) New insights into TGF-beta-Smad signalling. Trends in Biochemical Sciences 29, 265-273CrossRefGoogle ScholarPubMed
40Gonzalez-Nunez, M., Munoz-Felix, J.M. and Lopez-Novoa, J.M. (2013) The ALK-1/Smad1 pathway in cardiovascular physiopathology. A new target for therapy? Biochimica et Biophysica Acta 1832, 1492-1510CrossRefGoogle ScholarPubMed
41Sheen, Y.Y. et al. (2013) Targeting the transforming growth factor-beta signaling in cancer therapy. Biomolecules and Therapeutics (Seoul) 21, 323-331CrossRefGoogle ScholarPubMed
42Inman, G.J. et al. (2002) SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Molecular Pharmacology 62, 65-74CrossRefGoogle ScholarPubMed
43Goumans, M.J. et al. (2002) Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO Journal 21, 1743-1753CrossRefGoogle ScholarPubMed
44David, L. et al. (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109, 1953-1961CrossRefGoogle ScholarPubMed
45Ricard, N. et al. (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119, 6162-6171CrossRefGoogle ScholarPubMed
46Levet, S. et al. (2013) Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood 122, 598-607CrossRefGoogle ScholarPubMed
47ten Dijke, P. and Arthur, H.M. (2007) Extracellular control of TGFbeta signalling in vascular development and disease. Nature Reviews Molecular Cell Biology 8, 857-869CrossRefGoogle ScholarPubMed
48Massague, J. (2000) How cells read TGF-beta signals. Nature Reviews Molecular Cell Biology 1, 169-178CrossRefGoogle ScholarPubMed
49Moon, J.A. et al. (2006) IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney International 70, 1234-1243CrossRefGoogle ScholarPubMed
50Fukasawa, H. et al. (2004) Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proceedings of the National Academy of Sciences of the United States of America 101, 8687-8692CrossRefGoogle ScholarPubMed
51Wang, A. et al. (2007) Interference with TGF-beta signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria. American Journal of Physiology – Renal Physiology 293, F1657-F1665CrossRefGoogle ScholarPubMed
52Flanders, K.C. (2004) Smad3 as a mediator of the fibrotic response. International Journal of Experimental Pathology 85, 47-64CrossRefGoogle ScholarPubMed
53Inazaki, K. et al. (2004) Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney International 66, 597-604CrossRefGoogle ScholarPubMed
54Munoz-Felix, J.M., Lopez-Novoa, J.M. and Martinez-Salgado, C. (2014) Heterozygous disruption of activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy. Kidney International 85, 319-332CrossRefGoogle Scholar
55Vindevoghel, L. et al. (1998) Smad-dependent transcriptional activation of human type VII collagen gene (COL7A1) promoter by transforming growth factor-beta. Journal of Biological Chemistry 273, 13053-13057CrossRefGoogle ScholarPubMed
56Finnson, K.W. et al. (2008) ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. Journal of Bone and Mineral Research 23, 896-906CrossRefGoogle ScholarPubMed
57Finnson, K.W. et al. (2010) Endoglin differentially regulates TGF-beta-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthritis Cartilage 18, 1518-1527CrossRefGoogle Scholar
58Blaney Davidson, E.N. et al. (2009) Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. Journal of Immunology 182, 7937-7945CrossRefGoogle ScholarPubMed
59Munoz-Felix, J.M. et al. (2014) ALK1 heterozygosity increases extracellular matrix protein expression, proliferation and migration in fibroblasts. Biochimica et Biophysica Acta 1843, 1111-1122CrossRefGoogle ScholarPubMed
60Abe, H. et al. (2011) Role of Smad1 in diabetic nephropathy: molecular mechanisms and implications as a diagnostic marker. Histology and Histopathology 26, 531-541Google ScholarPubMed
61Scharpfenecker, M. et al. (2011) ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney. Radiotherapy and Oncology 99, 349-355CrossRefGoogle ScholarPubMed
62Pannu, J. et al. (2007) Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. Journal of Biological Chemistry 282, 10405-10413CrossRefGoogle ScholarPubMed
63Zeisberg, M. and Kalluri, R. (2008) Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatric Nephrology 23, 1395-1398CrossRefGoogle ScholarPubMed
64Manson, S.R. et al. (2011) The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. Journal of Urology 185 (6 Suppl), 2523-2530CrossRefGoogle ScholarPubMed
65Massague, J. (2012) TGFbeta signalling in context. Nature Reviews Molecular Cell Biology 13, 616-630CrossRefGoogle ScholarPubMed
66Martinez-Salgado, C., Rodriguez-Pena, A.B. and Lopez-Novoa, J.M. (2008) Involvement of small Ras GTPases and their effectors in chronic renal disease. Cellular and Molecular Life Sciences 65, 477-492CrossRefGoogle ScholarPubMed
67Nakerakanti, S. and Trojanowska, M. (2012) The role of TGF-beta receptors in fibrosis. Open Rheumatology Journal 6, 156-162CrossRefGoogle ScholarPubMed
68Cucoranu, I. et al. (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circulation Research 97, 900-907CrossRefGoogle ScholarPubMed
69Jiang, J.X. et al. (2012) Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radical Biology and Medicine 53, 289-296CrossRefGoogle ScholarPubMed
70Jiang, F. et al. (2014) NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. Redox Biology 2, 267-272CrossRefGoogle ScholarPubMed
71Goumans, M.J., Liu, Z. and ten Dijke, P. (2009) TGF-beta signaling in vascular biology and dysfunction. Cell Research 19, 116-127CrossRefGoogle ScholarPubMed
72Roy-Chaudhury, P., Simpson, J.G. and Power, D.A. (1997) Endoglin, a transforming growth factor-beta-binding protein, is upregulated in chronic progressive renal disease. Experimental Nephrology 5, 55-60Google ScholarPubMed
73Rodriguez-Pena, A. et al. (2001) Up-regulation of endoglin, a TGF-beta-binding protein, in rats with experimental renal fibrosis induced by renal mass reduction. Nephrology Dialysis Transplantation 16, 34-39CrossRefGoogle ScholarPubMed
74Rodriguez-Barbero, A. et al. (2001) Endoglin expression in human and rat mesangial cells and its upregulation by TGF-beta1. Biochemical and Biophysical Research Communications 282, 142-147CrossRefGoogle ScholarPubMed
75Lopez-Novoa, J.M. and Bernabeu, C. (2010) The physiological role of endoglin in the cardiovascular system. American Journal of Physiology – Heart and Circulatory Physiology 299, H959-H974CrossRefGoogle ScholarPubMed
76Bourdeau, A. et al. (2000) Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. American Journal of Pathology 156, 911-923CrossRefGoogle ScholarPubMed
77Lastres, P. et al. (1996) Endoglin modulates cellular responses to TGF-beta 1. Journal of Cell Biology 133, 1109-1121CrossRefGoogle ScholarPubMed
78Robledo, M.M. et al. (1998) Differential use of very late antigen-4 and -5 integrins by hematopoietic precursors and myeloma cells to adhere to transforming growth factor-beta1-treated bone marrow stroma. Journal of Biological Chemistry 273, 12056-12060CrossRefGoogle ScholarPubMed
79Conley, B.A. et al. (2000) Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis 153, 323-335CrossRefGoogle ScholarPubMed
80St-Jacques, S. et al. (1994) Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biology of Reproduction 51, 405-413CrossRefGoogle ScholarPubMed
81Gu, Y., Lewis, D.F. and Wang, Y. (2008) Placental productions and expressions of soluble endoglin, soluble fms-like tyrosine kinase receptor-1, and placental growth factor in normal and preeclamptic pregnancies. Journal of Clinical Endocrinology and Metabolism 93, 260-266CrossRefGoogle ScholarPubMed
82Diez-Marques, L. et al. (2002) Expression of endoglin in human mesangial cells: modulation of extracellular matrix synthesis. Biochimica et Biophysica Acta 1587, 36-44CrossRefGoogle ScholarPubMed
83Chen, K. et al. (2004) Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II. Circulation Research 95, 1167-1173CrossRefGoogle ScholarPubMed
84Leask, A. et al. (2002) Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis and Rheumatology 46, 1857-1865CrossRefGoogle ScholarPubMed
85Meurer, S.K. et al. (2005) Identification of endoglin in rat hepatic stellate cells: new insights into transforming growth factor beta receptor signaling. Journal of Biological Chemistry 280, 3078-3087CrossRefGoogle ScholarPubMed
86Meurer, S.K. et al. (2011) Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling. Cellular Signalling 23, 683-699CrossRefGoogle ScholarPubMed
87McAllister, K.A. et al. (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genetics 8, 345-351CrossRefGoogle ScholarPubMed
88Abdalla, S.A. and Letarte, M. (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. Journal of Medical Genetics 43, 97-110CrossRefGoogle ScholarPubMed
89Llorca, O. et al. (2007) Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. Journal of Molecular Biology 365, 694-705CrossRefGoogle ScholarPubMed
90Blanco, F.J. and Bernabeu, C. (2011) Alternative splicing factor or splicing factor-2 plays a key role in intron retention of the endoglin gene during endothelial senescence. Aging Cell 10, 896-907CrossRefGoogle ScholarPubMed
91Lastres, P. et al. (1994) Phosphorylation of the human-transforming-growth-factor-beta-binding protein endoglin. Biochemical Journal 301 (Pt 3), 765-768CrossRefGoogle ScholarPubMed
92Perez-Gomez, E. et al. (2005) Characterization of murine S-endoglin isoform and its effects on tumor development. Oncogene 24, 4450-4461CrossRefGoogle ScholarPubMed
93Bellon, T. et al. (1993) Identification and expression of two forms of the human transforming growth factor-beta-binding protein endoglin with distinct cytoplasmic regions. European Journal of Immunology 23, 2340-2345CrossRefGoogle ScholarPubMed
94Paquet, M.E. et al. (2001) Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function. Human Molecular Genetics 10, 1347-1357CrossRefGoogle ScholarPubMed
95Venkatesha, S. et al. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Medicine 12, 642-649CrossRefGoogle Scholar
96Blazquez-Medela, A.M. et al. (2010) Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Medicine 8, 86CrossRefGoogle ScholarPubMed
97Perez-Gomez, E. et al. (2010) The role of the TGF-beta coreceptor endoglin in cancer. Scientific World Journal 10, 2367-2384CrossRefGoogle ScholarPubMed
98Hawinkels, L.J. et al. (2010) Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Research 70, 4141-4150CrossRefGoogle ScholarPubMed
99Nassiri, F. et al. (2011) Endoglin (CD105): a review of its role in angiogenesis and tumor diagnosis, progression and therapy. Anticancer Research 31, 2283-2290Google ScholarPubMed
100Lastres, P. et al. (1992) Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. European Journal of Immunology 22, 393-397CrossRefGoogle ScholarPubMed
101Sanchez-Elsner, T. et al. (2002) Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. Journal of Biological Chemistry 277, 43799-43808CrossRefGoogle ScholarPubMed
102Botella, L.M. et al. (2001) Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-beta stimulation. Journal of Biological Chemistry 276, 34486-34494CrossRefGoogle ScholarPubMed
103Botella, L.M. et al. (2002) Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100, 4001-4010CrossRefGoogle ScholarPubMed
104Botella, L.M. et al. (2009) TGF-beta regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3–Sp1–KLF6 interaction. Biochemical Journal 419, 485-495CrossRefGoogle ScholarPubMed
105ten Dijke, P., Goumans, M.J. and Pardali, E. (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis 11, 79-89CrossRefGoogle ScholarPubMed
106Weiskirchen, R. and Meurer, S.K. (2013) BMP-7 counteracting TGF-beta1 activities in organ fibrosis. Frontiers in Bioscience (Landmark Ed) 18, 1407-1434CrossRefGoogle ScholarPubMed
107Bernabeu, C., Conley, B.A. and Vary, C.P. (2007) Novel biochemical pathways of endoglin in vascular cell physiology. Journal of Cellular Biochemistry 102, 1375-1388CrossRefGoogle ScholarPubMed
108Bobik, A. (2006) Transforming growth factor-betas and vascular disorders. Arteriosclerosis Thrombosis and Vascular Biology 26, 1712-1720CrossRefGoogle ScholarPubMed
109Goumans, M.J. and Mummery, C. (2000) Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. International Journal of Developmental Biology 44, 253-265Google ScholarPubMed
110Bernabeu, C., Lopez-Novoa, J.M. and Quintanilla, M. (2009) The emerging role of TGF-beta superfamily coreceptors in cancer. Biochimica et Biophysica Acta 1792, 954-973CrossRefGoogle ScholarPubMed
111Ray, B.N. et al. (2010) ALK5 phosphorylation of the endoglin cytoplasmic domain regulates Smad1/5/8 signaling and endothelial cell migration. Carcinogenesis 31, 435-441CrossRefGoogle ScholarPubMed
112Lebrin, F. et al. (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO Journal 23, 4018-4028CrossRefGoogle ScholarPubMed
113Lee, N.Y. et al. (2008) Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. Journal of Biological Chemistry 283, 32527-32533CrossRefGoogle ScholarPubMed
114Santibanez, J.F. et al. (2007) Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. Journal of Cellular Physiology 210, 456-468CrossRefGoogle ScholarPubMed
115Velasco, S. et al. (2008) L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. Journal of Cell Science 121(Pt 6), 913-919CrossRefGoogle ScholarPubMed
116O'Connor, J.C. et al. (2007) Coculture with prostate cancer cells alters endoglin expression and attenuates transforming growth factor-beta signaling in reactive bone marrow stromal cells. Molecular Cancer Research 5, 585-603CrossRefGoogle ScholarPubMed
117Parker, W.L., Goldring, M.B. and Philip, A. (2003) Endoglin is expressed on human chondrocytes and forms a heteromeric complex with betaglycan in a ligand and type II TGFbeta receptor independent manner. Journal of Bone and Mineral Research 18, 289-302CrossRefGoogle Scholar
118Kapur, N.K. et al. (2012) Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation 125, 2728-2738CrossRefGoogle ScholarPubMed
119Cruz-Gonzalez, I. et al. (2008) Identification of serum endoglin as a novel prognostic marker after acute myocardial infarction. Journal of Cellular and Molecular Medicine 12, 955-961CrossRefGoogle ScholarPubMed
120Salem, D. et al. (2012) The combination of endoglin and FIB-4 increases the accuracy of detection of hepatic fibrosis in chronic hepatitis C patients. Open Journal of Gastroenterology 2, 66-67CrossRefGoogle Scholar
121Clemente, M. et al. (2006) Increased intrahepatic and circulating levels of endoglin, a TGF-beta1 co-receptor, in patients with chronic hepatitis C virus infection: relationship to histological and serum markers of hepatic fibrosis. Journal of Viral Hepatitis 13, 625-632CrossRefGoogle ScholarPubMed
122Burke, J.P. et al. (2010) Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts. British Journal of Surgery 97, 892-901CrossRefGoogle ScholarPubMed
123Dharmapatni, A.A. et al. (2001) The TGF beta receptor endoglin in systemic sclerosis. Asian Pacific Journal of Allergy and Immunology 19, 275-282Google ScholarPubMed
124Holmes, A.M. et al. (2011) Elevated CCN2 expression in scleroderma: a putative role for the TGFbeta accessory receptors TGFbetaRIII and endoglin. Journal of Cell Communication and Signalling 5, 173-177CrossRefGoogle ScholarPubMed
125Morris, E. et al. (2011) Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts. Journal of Cellular Physiology 226, 3340-3348CrossRefGoogle ScholarPubMed
126Obreo, J. et al. (2004) Endoglin expression regulates basal and TGF-beta1-induced extracellular matrix synthesis in cultured L6E9 myoblasts. Cellular Physiology and Biochemistry 14, 301-310CrossRefGoogle ScholarPubMed
127Rodriguez-Barbero, A. et al. (2006) Endoglin modulation of TGF-beta1-induced collagen synthesis is dependent on ERK1/2 MAPK activation. Cellular Physiology and Biochemistry 18, 135-142CrossRefGoogle ScholarPubMed
128Guerrero-Esteo, M. et al. (1999) Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts. European Journal of Cell Biology 78, 614-623CrossRefGoogle ScholarPubMed
129Pericacho, M. et al. (2013) Endoglin haploinsufficiency promotes fibroblast accumulation during wound healing through Akt activation. PLoS ONE 8, e54687CrossRefGoogle ScholarPubMed
130Perez-Gomez, E. et al. (2014) Impaired wound repair in adult endoglin heterozygous mice associated with lower NO bioavailability. Journal of Investigative Dermatology 134, 247-255CrossRefGoogle ScholarPubMed
131Meurer, S.K. et al. (2013) Overexpression of endoglin modulates TGF-beta1-signalling pathways in a novel immortalized mouse hepatic stellate cell line. PLoS ONE 8, e56116CrossRefGoogle Scholar
132Shen, H. et al. (2003) Transforming growth factor-beta1 downregulation of Smad1 gene expression in rat hepatic stellate cells. American Journal of Physiology – Gastrointestinal and Liver Physiology 285, G539-G546CrossRefGoogle ScholarPubMed
133Shen, A. et al. (2007) Study on the in vitro and in vivo activation of rat hepatic stellate cells by Raman spectroscopy. Journal of Biomedical Optics 12, 034003CrossRefGoogle Scholar
134Wiercinska, E. et al. (2006) Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology 43, 1032-1041CrossRefGoogle ScholarPubMed
135Meurer, S.K. et al. (2014) Endoglin in liver fibrogenesis: bridging basic science and clinical practice. World Journal of Biological Chemistry 5, 180-203Google ScholarPubMed
136Scherner, O. et al. (2007) Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling. Journal of Biological Chemistry 282, 13934-13943CrossRefGoogle ScholarPubMed
137Bascands, J.L. and Schanstra, J.P. (2005) Obstructive nephropathy: insights from genetically engineered animals. Kidney International 68, 925-937CrossRefGoogle ScholarPubMed
138Kaneto, H., Morrissey, J. and Klahr, S. (1993) Increased expression of TGF-beta 1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation. Kidney International 44, 313-321CrossRefGoogle ScholarPubMed
139Wang, B.W. et al. (2014) MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart. PLoS ONE 9, e84188Google ScholarPubMed
140Higgins, D.F. et al. (2008) Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle 7, 1128-1132CrossRefGoogle ScholarPubMed
141Prieto, M. et al. (2005) Effect of the long-term treatment with trandolapril on endoglin expression in rats with experimental renal fibrosis induced by renal mass reduction. Kidney Blood Pressure Research 28, 32-40CrossRefGoogle ScholarPubMed
142Ucero, A.C. et al. (2014) Unilateral ureteral obstruction: beyond obstruction. International Urology and Nephrology 46, 765-776CrossRefGoogle ScholarPubMed
143Grande, M.T., Perez-Barriocanal, F. and Lopez-Novoa, J.M. (2010) Role of inflammation in tubulo-interstitial damage associated to obstructive nephropathy. Journal of Inflammation (London) 7, 19CrossRefGoogle Scholar
144Docherty, N.G. et al. (2006) Endoglin regulates renal ischaemia-reperfusion injury. Nephrology Dialysis Transplantation 21, 2106-2119CrossRefGoogle ScholarPubMed
145Rossi, E. et al. (2013) Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration. Blood 121, 403-415CrossRefGoogle ScholarPubMed
146Scharpfenecker, M. et al. (2012) The TGF-beta co-receptor endoglin regulates macrophage infiltration and cytokine production in the irradiated mouse kidney. Radiotherapy and Oncology 105, 313-320CrossRefGoogle ScholarPubMed
147Rodriguez-Barbero, A. et al. (2000) Potential use of isolated glomeruli and cultured mesangial cells as in vitro models to assess nephrotoxicity. Cell Biology and Toxicology 16, 145-153CrossRefGoogle ScholarPubMed
148Martinez-Salgado, C. et al. (2004) Gentamicin treatment induces simultaneous mesangial proliferation and apoptosis in rats. Kidney International 65, 2161-2171CrossRefGoogle ScholarPubMed
149Fujimoto, M. et al. (2003) Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochemical and Biophysical Research Communications 305, 1002-1007CrossRefGoogle ScholarPubMed
150Wang, B. et al. (2007) Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts. American Journal of Physiology – Heart and Circulatory Physiology 293, H1282-H1290CrossRefGoogle ScholarPubMed
151Abe, H. et al. (2004) Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. Journal of Biological Chemistry 279, 14201-14206CrossRefGoogle ScholarPubMed
152Matsubara, T. et al. (2006) Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Laboratory Investigation 86, 357-368CrossRefGoogle ScholarPubMed
153Zeisberg, M. and Duffield, J.S. (2010) Resolved: EMT produces fibroblasts in the kidney. J American Society of Nephrology 21, 1247-1253CrossRefGoogle ScholarPubMed
154Zeisberg, M. et al. (2001) Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. American Journal of Pathology 159, 1313-1321CrossRefGoogle ScholarPubMed
155Strutz, F. and Zeisberg, M. (2006) Renal fibroblasts and myofibroblasts in chronic kidney disease. J American Society of Nephrology 17, 2992-2998CrossRefGoogle ScholarPubMed
156Lara, P.C. et al. (1996) Radiation-induced differentiation of human skin fibroblasts: relationship with cell survival and collagen production. International Journal of Radiation Biology 70, 683-692CrossRefGoogle ScholarPubMed
157Rodemann, H.P. and Muller, G.A. (1991) Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. American Journal of Kidney Diseases 17, 684-686CrossRefGoogle Scholar
158Scharpfenecker, M. et al. (2009) Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys. Radiotherapy and Oncology 92, 484-491CrossRefGoogle ScholarPubMed
159Scharpfenecker, M. et al. (2013) Endoglin haploinsufficiency attenuates radiation-induced deterioration of kidney function in mice. Radiotherapy and Oncology 108, 464-468CrossRefGoogle ScholarPubMed
160Hawinkels, L.J. and Ten Dijke, P. (2011) Exploring anti-TGF-beta therapies in cancer and fibrosis. Growth Factors 29, 140-152CrossRefGoogle ScholarPubMed
161Weiskirchen, R. et al. (2009) BMP-7 as antagonist of organ fibrosis. Frontiers in Bioscience (Landmark Ed) 14, 4992-5012CrossRefGoogle ScholarPubMed
162Castonguay, R. et al. (2011) Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. Journal of Biological Chemistry 286, 30034-30046CrossRefGoogle ScholarPubMed
163Mahmoud, M. et al. (2010) Pathogenesis of arteriovenous malformations in the absence of endoglin. Circulation Research 106, 1425-1433CrossRefGoogle ScholarPubMed
164Seon, B.K. et al. (2011) Endoglin-targeted cancer therapy. Current Drug Delivery 8, 135-143CrossRefGoogle ScholarPubMed
165Uneda, S. et al. (2009) Anti-endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature. International Journal of Cancer 125, 1446-1453CrossRefGoogle ScholarPubMed
166Bhatt, R.S. and Atkins, M.B. (2014) Molecular pathways: can activin-like kinase pathway inhibition enhance the limited efficacy of VEGF inhibitors? Clinical Cancer Research 20, 2838-2845CrossRefGoogle ScholarPubMed