title: L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction.
abstract: Transforming growth factor-β (TGF-β) plays a pivotal role in renal fibrosis. Endoglin, a 180 KDa membrane glycoprotein, is a TGF-β co-receptor overexpressed in several models of chronic kidney disease, but its function in renal fibrosis remains uncertain. Two membrane isoforms generated by alternative splicing have been described, L-Endoglin (long) and S-Endoglin (short) that differ from each other in their cytoplasmic tails, being L-Endoglin the most abundant isoform. The aim of this study was to assess the effect of L-Endoglin overexpression in renal tubulo-interstitial fibrosis. For this purpose, a transgenic mouse which ubiquitously overexpresses human L-Endoglin (L-ENG+) was generated and unilateral ureteral obstruction (UUO) was performed in L-ENG+ mice and their wild type (WT) littermates. Obstructed kidneys from L-ENG+ mice showed higher amounts of type I collagen and fibronectin but similar levels of α-smooth muscle actin (α-SMA) than obstructed kidneys from WT mice. Smad1 and Smad3 phosphorylation were significantly higher in obstructed kidneys from L-ENG+ than in WT mice. Our results suggest that the higher increase of renal fibrosis observed in L-ENG+ mice is not due to a major abundance of myofibroblasts, as similar levels of α-SMA were observed in both L-ENG+ and WT mice, but to the higher collagen and fibronectin synthesis by these fibroblasts. Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development.
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Oujo
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Muñoz-Félix
authors.affiliation: Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; Institute Queen Sophie for Renal Research, Salamanca, Spain; Department of Human Anatomy and Histology, University of Salamanca, Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arévalo
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Núñez-Gómez
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Pérez-Roque
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pericacho
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-Núñez
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Langa
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain; Health Sciences Studies Institute of Castilla y León (IESCYL), Salamanca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Salgado
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Perez-Barriocanal
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
authors.affiliation: Renal and Cardiovascular Research 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, Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Lopez-Novoa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D000071063:Endoglin; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D005353:Fibronectins; D011956:Receptors, Cell Surface; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen