L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction.

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

doi:10.1371/journal.pone.0110365

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.

Highlights

Chronic kidney disease (CKD) is a pathology that affects nearly 10% of the population
Our results suggest that L-Endoglin overexpression is associated to increased renal fibrosis after ureteral obstruction (UUO) mainly due to the enhanced ability of renal myofibroblasts to synthesize extracellular matrix (ECM) components
Endoglin haploinsufficiency does not seem to affect the fibrosis induced in the UUO model [12]

Summary

Introduction

Chronic kidney disease (CKD) is a pathology that affects nearly 10% of the population. This illness is characterized by a progressive decrease in glomerular filtration rate that eventually leads to renal failure. TGF-b is able to signal through ALK1-Smad1/5 or ALK5Smad2/3 pathways, resulting in different cell responses [4]. It is traditionally accepted that TGF-b1 exerts its profibrotic effects through the ALK5 pathway [5]. Smad pathway activation has been recently associated with renal fibrosis in diabetic and obstructive nephropathy [6,7]. In vitro experiments have shown that endoglin antagonizes the profibrotic effect of TGF-b [9,10]. Endoglin involvement has been studied in other fibrotic pathologies such as scleroderma [14], hepatic fibrosis [15] or cardiac fibrosis [16,17]

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