Oujo Bárbara, Muñoz-Félix José M, Arévalo Miguel, Núñez-Gómez Elena, Pérez-Roque Lucía, Pericacho Miguel, González-Núñez María, Langa Carmen, Martínez-Salgado Carlos, Perez-Barriocanal Fernando, Bernabeu Carmelo, Lopez-Novoa José M
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.
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.
PLoS One. 2014 Oct 14;9(10):e110365. doi: 10.1371/journal.pone.0110365. eCollection 2014.
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.
转化生长因子-β（TGF-β）在肾纤维化中起关键作用。内皮糖蛋白是一种180 kDa的膜糖蛋白，是一种TGF-β共受体，在几种慢性肾病模型中过表达，但其在肾纤维化中的功能仍不确定。已描述了由可变剪接产生的两种膜异构体，L-内皮糖蛋白（长型）和S-内皮糖蛋白（短型），它们的胞质尾部不同，L-内皮糖蛋白是最丰富的异构体。本研究的目的是评估L-内皮糖蛋白过表达对肾小管间质纤维化的影响。为此，构建了一种普遍过表达人L-内皮糖蛋白的转基因小鼠（L-ENG+），并对L-ENG+小鼠及其野生型（WT）同窝小鼠进行单侧输尿管梗阻（UUO）。与WT小鼠的梗阻肾脏相比，L-ENG+小鼠的梗阻肾脏显示出更高水平的I型胶原蛋白和纤连蛋白，但α-平滑肌肌动蛋白（α-SMA）水平相似。L-ENG+小鼠梗阻肾脏中Smad1和Smad3的磷酸化水平明显高于WT小鼠。我们的结果表明，L-ENG+小鼠中观察到的肾纤维化更高程度的增加并非由于肌成纤维细胞数量的大量增加，因为在L-ENG+和WT小鼠中观察到的α-SMA水平相似，而是由于这些成纤维细胞更高的胶原蛋白和纤连蛋白合成。此外，体内L-内皮糖蛋白过表达增强了Smad1和Smad3信号通路，这种效应与更高程度的肾纤维化发展相关。
