L-Endoglin Overexpression Increases Renal Fibrosis after Unilateral Ureteral Obstruction

Transforming growth factor-beta (TGF-beta) plays a pivotal role in renal fibrosis. Endoglin, a 180 KDa membrane glycoprotein, is a TGF-beta 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 alpha-smooth muscle actin (alpha-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 alpha-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.