Endoglin Upregulation During Experimental Renal Interstitial Fibrosis in Mice

Rodríguez-Peña, Ana B.; Eleno, Nélida; Düwell, Anette; Arévalo, Miguel; Pérez‐Barriocanal, Fernando; Flores, Olga; Docherty, Neil G.; Bernabeu, Carmelo; Letarte, Michelle; López‐Novoa, José M.

doi:10.1161/01.hyp.0000037429.73954.27

Cited by 71 publications

(86 citation statements)

References 42 publications

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“…This study also detected a marked increase in hepatic endoglin expression after BDL. These results agree with previous studies reporting endoglin overexpression in animal models of organ fibrosis [27,28]. After BDL, endoglin is clearly expressed in non-parenchymal cells.…”

Section: Discussionsupporting

confidence: 93%

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Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats

Pérez‐Barriocanal¹

2011

TOGASJ

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Abstract:Background: Transforming growth factor beta 1 (TGF-1) has been implicated in the stimulation of extracellular matrix synthesis in acute and chronic liver disease. Endoglin (CD-105) is a membrane glycoprotein that binds TGF-1 with high affinity. Endoglin is overexpressed in several model of fibrosis. The goal of the present study was to evaluate the effect of bile duct ligation (BDL) on endoglin expression and the effect of endoglin overexpression on liver fibrosis in rats.Methods: Rat livers were transfected with a vector containing full length human endoglin (h-end) or an empty vector (mock) and 48 hours after were subjected to either BDL or sham operation (SO). Eighteen days after, a blood sample was obtained and bilirubin and serum enzyme activities were measured to assess liver damage. Liver fibrosis was quantified by a computer-assisted image analysis of Sirius red stained livers and by liver hydroxyproline content. Endoglin expression in the liver tissue was assessed by Western blot and immunohystochemistry.Results: Both immunohistochemistry and Western blot reveals endoglin upregulation after BDL in rats. In addition, these techniques also reveal effective human endoglin transfection in the rat's liver. After BDL, liver fibrosis and plasma levels of enzymes were similar in h-end transfected and mock-transfected rats. Western blots showed higher endoglin expression after BDL in h-end transfected and mock-transfected rats. Conclusions:The present study provides clear evidence that endoglin is upregulated in the liver of rats with BDL. h-end overexpression did not improve liver fibrosis after BDL in rats.

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Section: Discussionsupporting

confidence: 93%

“…Endoglin binds TGF-1 and TGF-3 with high affinity in human endothelial cells [25], in association with the type II receptor [26]. We have reported that endoglin is upregulated in several models of renal fibrosis in rats and mice [27,28]. Endoglin has been also shown to be upregulated in other fibrotic tissues [29,30].…”

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confidence: 99%

Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats

Pérez‐Barriocanal¹

2011

TOGASJ

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“…Northern blot experiments with a cDNA probe corresponding to the extracellular domain of the molecule (see Materials and methods) revealed a transcript of 3.1 kb in all the cell lines (Figure 3a), but detection required a long exposure of the autoradiography indicating a low level This transcript has already been described in other murine tissues such as the ovary, thymus, placenta, and kidney (Ge and Butcher, 1994;St-Jacques et al, 1994;Rodriguez-Pen˜a et al, 2002). The relative abundance of the endoglin mRNAs among the cell lines was roughly similar, except for PDV carcinoma cells that showed lower levels in this experiment.…”

Section: Endoglin Expression In Murine Keratinocyte Cell Linesmentioning

confidence: 76%

Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis

et al. 2003

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Endoglin is an integral membrane glycoprotein primarily expressed in the vascular endothelium, but also found on macrophages and stromal cells. It binds several members of the transforming growth factor (TGF)-b family of growth factors and modulates TGF-b 1 -dependent cellular responses. However, it lacks cytoplasmic signaling motifs and is considered as an auxiliary receptor for TGF-b. We show here that endoglin is expressed in mouse and human epidermis and in skin appendages, such as hair follicles and sweat glands, as determined by immunohistochemistry. In normal interfollicular epidermis, endoglin was restricted to basal keratinocytes and absent in differentiating cells of suprabasal layers. Follicular expression of endoglin was high in hair bulb keratinocytes, but decreased in parts distal from the bulb. To address the role of endoglin in skin carcinogenesis in vivo, Endoglin heterozygous mice were subjected to long-term chemical carcinogenesis treatment. Reduction in endoglin had a dual effect during multistage carcinogenesis, by inhibiting the early appearance of benign papillomas, but increasing malignant progression to highly undifferentiated carcinomas. Our results are strikingly similar to those previously reported for transgenic mice overexpressing TGF-b 1 in the epidermis. These data suggest that endoglin might attenuate TGF-b 1 signaling in normal epidermis and interfere with progression of skin carcinogenesis.

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“…[26][27][28] The main switch between these two pathways is provided by endoglin, 7,29,30 which itself is thought to be under regulatory control by TGF-b. 31,32 Under basal conditions, balance between both pathways exist through endoglin inhibition of Smad3 signaling and activation of Smad1. 33 However, it is unknown whether prolonged and intense TGF-b signaling in ECs is associated with the predominant switch to ALK5 pathway.…”

Section: Discussionmentioning

confidence: 99%

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Xavier

Vasko

Matsumoto

et al. 2015

Journal of the American Society of Nephrology

133

109

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Excessive TGF-b signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-b signaling on development of fibrosis, there is a lack of information on ablating TGF-b signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-b receptor knockout (TbRII endo+/2 ) mice to explore whether curtailed TGF-b signaling significantly modifies nephrosclerosis.These mice developed normally, but showed enhanced angiogenic potential compared with TbRII endo+/+ mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TbRII endo+/2 mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TbRII endo+/+ counterparts. In addition, partial deletion of TbRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-b-induced canonical Smad2 signaling was reduced in TbRII +/2 ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TbRII +/2 ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TbRII +/2 ECs compared with TbRII +/+ ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-b signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-b signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

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Endoglin Upregulation During Experimental Renal Interstitial Fibrosis in Mice

Cited by 71 publications

References 42 publications

Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats

Endoglin Upregulation in the Liver after Bile Duct Ligation in Rats

Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis

Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

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