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

Oujo B, Muñoz-Félix JM, Arévalo M, Núñez-Gómez E, Pérez-Roque L, Pericacho M, González-Núñez M, Langa C, Martínez-Salgado C, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM - PLoS ONE (2014)

Bottom Line: 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.Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development.

View Article: PubMed Central - PubMed

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.

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.

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Effect of L-Endoglin overexpression on interstitial fibrosis after unilateral ureteral obstruction (I).Representative images of haematoxylin-eosin (a) and Masson’s trichrome (b) staining in sham operated (SO), non-obstructed (NO) and obstructed (O) kidneys from WT and L-ENG+ mice. In O kidneys tubular dilatation, inflammatory cell infiltration and interstitial fibrosis can be observed. Bar = 100 µm.
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pone-0110365-g002: Effect of L-Endoglin overexpression on interstitial fibrosis after unilateral ureteral obstruction (I).Representative images of haematoxylin-eosin (a) and Masson’s trichrome (b) staining in sham operated (SO), non-obstructed (NO) and obstructed (O) kidneys from WT and L-ENG+ mice. In O kidneys tubular dilatation, inflammatory cell infiltration and interstitial fibrosis can be observed. Bar = 100 µm.

Mentions: After 15 days of UUO, obstructed kidneys in both, wild type and L-ENG+ mice, exhibited a severe hydronephrosis and the typical features of obstructive nephropathy. Thus, both hematoxylin-eosin and Masson’s trichrome staining revealed that the total thickness of the cortex and medulla was diminished and medullar compression was evidenced (Figure S2). In the cortex, tubules showed changes ranging from a dilated lumen with a flattened epithelium to necrosis of varying degrees. In most cases, an interstitial inflammatory infiltrate was observed, mainly in perivascular areas (Figure 2a). Fibrosis, detected with Masson’s trichrome staining, was irregularly distributed and more pronounced around blood vessels. Little or no tissue fibrosis was observed in non obstructed (NO) kidneys as compared with obstructed (O) kidneys. Obstructed kidneys from L-ENG+ mice had a high degree of fibrosis, according to Masson’s staining, than WT mice. Sham-operated animals had normal kidney histology (Figure 2b). Sirius red staining showed that O kidneys from L-ENG+ mice had a high degree of fibrosis compared to O kidneys from WT mice (Figure 3a, b). Morphometric studies performed in Sirius red-stained slides demonstrated that O kidneys from L-ENG+ mice had more renal area occupied by fibrosis than O kidneys from WT mice (Figure 3b).


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

Oujo B, Muñoz-Félix JM, Arévalo M, Núñez-Gómez E, Pérez-Roque L, Pericacho M, González-Núñez M, Langa C, Martínez-Salgado C, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM - PLoS ONE (2014)

Effect of L-Endoglin overexpression on interstitial fibrosis after unilateral ureteral obstruction (I).Representative images of haematoxylin-eosin (a) and Masson’s trichrome (b) staining in sham operated (SO), non-obstructed (NO) and obstructed (O) kidneys from WT and L-ENG+ mice. In O kidneys tubular dilatation, inflammatory cell infiltration and interstitial fibrosis can be observed. Bar = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196986&req=5

pone-0110365-g002: Effect of L-Endoglin overexpression on interstitial fibrosis after unilateral ureteral obstruction (I).Representative images of haematoxylin-eosin (a) and Masson’s trichrome (b) staining in sham operated (SO), non-obstructed (NO) and obstructed (O) kidneys from WT and L-ENG+ mice. In O kidneys tubular dilatation, inflammatory cell infiltration and interstitial fibrosis can be observed. Bar = 100 µm.
Mentions: After 15 days of UUO, obstructed kidneys in both, wild type and L-ENG+ mice, exhibited a severe hydronephrosis and the typical features of obstructive nephropathy. Thus, both hematoxylin-eosin and Masson’s trichrome staining revealed that the total thickness of the cortex and medulla was diminished and medullar compression was evidenced (Figure S2). In the cortex, tubules showed changes ranging from a dilated lumen with a flattened epithelium to necrosis of varying degrees. In most cases, an interstitial inflammatory infiltrate was observed, mainly in perivascular areas (Figure 2a). Fibrosis, detected with Masson’s trichrome staining, was irregularly distributed and more pronounced around blood vessels. Little or no tissue fibrosis was observed in non obstructed (NO) kidneys as compared with obstructed (O) kidneys. Obstructed kidneys from L-ENG+ mice had a high degree of fibrosis, according to Masson’s staining, than WT mice. Sham-operated animals had normal kidney histology (Figure 2b). Sirius red staining showed that O kidneys from L-ENG+ mice had a high degree of fibrosis compared to O kidneys from WT mice (Figure 3a, b). Morphometric studies performed in Sirius red-stained slides demonstrated that O kidneys from L-ENG+ mice had more renal area occupied by fibrosis than O kidneys from WT mice (Figure 3b).

Bottom Line: 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.Furthermore, in vivo L-Endoglin overexpression potentiates Smad1 and Smad3 pathways and this effect is associated with higher renal fibrosis development.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus