Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling
Background: Peritoneal fibrosis (PF) is an intractable complication in patients on long-term peritoneal dialysis (PD). Transforming growth factor-β (TGF-β) is a key pro-fibrogenic factor involved in PD-associated PF, and endoglin, as a coreceptor for TGF-β, plays a role in balancing the TGF-β signal...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.973182/full |
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| author | Qian Huang Rui Xiao Jing Lu Yao Zhang Liang Xu Jie Gao Jing Sun Jing Sun Haiping Wang Haiping Wang |
| author_facet | Qian Huang Rui Xiao Jing Lu Yao Zhang Liang Xu Jie Gao Jing Sun Jing Sun Haiping Wang Haiping Wang |
| author_sort | Qian Huang |
| collection | DOAJ |
| description | Background: Peritoneal fibrosis (PF) is an intractable complication in patients on long-term peritoneal dialysis (PD). Transforming growth factor-β (TGF-β) is a key pro-fibrogenic factor involved in PD-associated PF, and endoglin, as a coreceptor for TGF-β, plays a role in balancing the TGF-β signaling pathway. Here, we investigated whether endoglin could be a potential therapeutic target for PF.Methods:In vivo, we established PF model in SD rats by daily intraperitoneal injection of peritoneal dialysis fluids (PDF) containing 4.25% glucose for 6 weeks and downregulated endoglin expression by tail vein injection of AAV9-ENG on day 14 to assess the effect of endoglin on peritoneal morphology and markers related to fibrosis, angiogenesis, and epithelial-mesenchymal transition (EMT). In vitro, we treated human peritoneal mesothelial cells (HPMCs) transfected with ENG siRNA in high glucose medium to explore the potential mechanism of endoglin in PF.Results: Compared to control group, continuous exposure to biologically incompatible PDF induced exacerbated PF, accompanied by a significant increase in endoglin expression. Conversely, knockdown of endoglin ameliorated peritoneal injury characterized by increased peritoneal thickening and collagen deposition, angiogenesis, as well as EMT. Consistently, HPMCs cultured in high glucose medium underwent the EMT process and exhibited over-expression of fibronectin, collagen type I, vascular endothelial growth factor (VEGF), whereas these aforementioned alterations were alleviated after ENG siRNA transfection. In addition, we also found that ENG siRNA inhibited TGF-β-induced phosphorylation of Smad2/3 and Smad1/5/9 in HPMCs treated with high glucose (HG).Conclusion: Our findings confirmed for the first time that endoglin exacerbated PF by regulating the activation of TGF-β/ALK/Smads signaling, which will provide a novel potential therapeutic target in PF. |
| format | Article |
| id | doaj-art-eab4cd1a93754b6a8e1a9f1230d4b365 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-eab4cd1a93754b6a8e1a9f1230d4b3652025-08-20T02:34:24ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.973182973182Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signalingQian Huang0Rui Xiao1Jing Lu2Yao Zhang3Liang Xu4Jie Gao5Jing Sun6Jing Sun7Haiping Wang8Haiping Wang9Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, ChinaDepartment of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaBackground: Peritoneal fibrosis (PF) is an intractable complication in patients on long-term peritoneal dialysis (PD). Transforming growth factor-β (TGF-β) is a key pro-fibrogenic factor involved in PD-associated PF, and endoglin, as a coreceptor for TGF-β, plays a role in balancing the TGF-β signaling pathway. Here, we investigated whether endoglin could be a potential therapeutic target for PF.Methods:In vivo, we established PF model in SD rats by daily intraperitoneal injection of peritoneal dialysis fluids (PDF) containing 4.25% glucose for 6 weeks and downregulated endoglin expression by tail vein injection of AAV9-ENG on day 14 to assess the effect of endoglin on peritoneal morphology and markers related to fibrosis, angiogenesis, and epithelial-mesenchymal transition (EMT). In vitro, we treated human peritoneal mesothelial cells (HPMCs) transfected with ENG siRNA in high glucose medium to explore the potential mechanism of endoglin in PF.Results: Compared to control group, continuous exposure to biologically incompatible PDF induced exacerbated PF, accompanied by a significant increase in endoglin expression. Conversely, knockdown of endoglin ameliorated peritoneal injury characterized by increased peritoneal thickening and collagen deposition, angiogenesis, as well as EMT. Consistently, HPMCs cultured in high glucose medium underwent the EMT process and exhibited over-expression of fibronectin, collagen type I, vascular endothelial growth factor (VEGF), whereas these aforementioned alterations were alleviated after ENG siRNA transfection. In addition, we also found that ENG siRNA inhibited TGF-β-induced phosphorylation of Smad2/3 and Smad1/5/9 in HPMCs treated with high glucose (HG).Conclusion: Our findings confirmed for the first time that endoglin exacerbated PF by regulating the activation of TGF-β/ALK/Smads signaling, which will provide a novel potential therapeutic target in PF.https://www.frontiersin.org/articles/10.3389/fphar.2022.973182/fullendoglinperitoneal fibrosisangiogenesisEMTTGF-β/ALK/Smads |
| spellingShingle | Qian Huang Rui Xiao Jing Lu Yao Zhang Liang Xu Jie Gao Jing Sun Jing Sun Haiping Wang Haiping Wang Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling Frontiers in Pharmacology endoglin peritoneal fibrosis angiogenesis EMT TGF-β/ALK/Smads |
| title | Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling |
| title_full | Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling |
| title_fullStr | Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling |
| title_full_unstemmed | Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling |
| title_short | Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling |
| title_sort | endoglin aggravates peritoneal fibrosis by regulating the activation of tgf β alk smads signaling |
| topic | endoglin peritoneal fibrosis angiogenesis EMT TGF-β/ALK/Smads |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.973182/full |
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