L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction

Bárbara Oujo; José M Muñoz-Félix; Miguel Arévalo; Elena Núñez-Gómez; Lucía Pérez-Roque; Miguel Pericacho; María González-Núñez; Carmen Langa; Carlos Martínez-Salgado; Fernando Perez-Barriocanal; Carmelo Bernabeu; José M Lopez-Novoa

doi:10.1371/journal.pone.0110365

L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction

PLoS One. 2014 Oct 14;9(10):e110365. doi: 10.1371/journal.pone.0110365. eCollection 2014.

Affiliations

¹ 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.
² 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.
³ Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics*
Collagen / metabolism
Disease Models, Animal
Endoglin
Extracellular Matrix / metabolism
Fibronectins
Fibrosis
Gene Expression*
Humans
Kidney Diseases / etiology*
Kidney Diseases / metabolism
Kidney Diseases / pathology*
Mice
Mice, Transgenic
Myofibroblasts / metabolism
Myofibroblasts / pathology
Receptors, Cell Surface / genetics*
Signal Transduction / drug effects
Smad Proteins / metabolism
Transforming Growth Factor beta / metabolism
Ureteral Obstruction / complications*

Substances

Antigens, CD
ENG protein, human
Endoglin
Fibronectins
Receptors, Cell Surface
Smad Proteins
Transforming Growth Factor beta
Collagen

Grants and funding

This study was supported by grants from Ministerio de Economia y Competitividad of Spain (SAF2010-19222 to CB and SAF2010-15881 to JML-N), Instituto de Salud Carlos III (Ministerio de Economia y Competitividad, PS09/01067 to CM-S), Junta de Castilla y Leon (GR100 to JML-N), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, CB) and Red de Investigación Cooperativa en Enfermedades Renales (RD12/0021/0032; REDINREN, to JML-N). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds. The Cardiovascular Phenotyping Unit of the University of Salamanca, including the telemetry equipment, was acquired with the support of the European Regional Development Funds (FEDER). BO and EN-G are supported by Ministerio de Economía y Competitividad; JMM-F and LP-R are supported by Junta de Castilla y León and Fondo Social Europeo. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.