UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway
Abstract Renal fibrosis is widely recognized as the ultimate outcome of many chronic kidney diseases. The process of epithelial-mesenchymal transition (EMT) plays a critical role in the progression of fibrosis following renal injury. UHRF1, as a critical epigenetic regulator, may play an essential r...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-86496-9 |
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| author | Lijie Yang Penghui Si Tuoheti Kuerban Linfa Guo Shanzhi Zhan Yisha Zuhaer Yingtong Zuo Peixiang Lu Xiaojie Bai Tongzu Liu |
| author_facet | Lijie Yang Penghui Si Tuoheti Kuerban Linfa Guo Shanzhi Zhan Yisha Zuhaer Yingtong Zuo Peixiang Lu Xiaojie Bai Tongzu Liu |
| author_sort | Lijie Yang |
| collection | DOAJ |
| description | Abstract Renal fibrosis is widely recognized as the ultimate outcome of many chronic kidney diseases. The process of epithelial-mesenchymal transition (EMT) plays a critical role in the progression of fibrosis following renal injury. UHRF1, as a critical epigenetic regulator, may play an essential role in the pathogenesis and progression of renal fibrosis and EMT. However, the potential mechanisms remain to be elucidated. We aim to investigate the role of UHRF1 in EMT and renal fibrosis and to evaluate the potential benefits of Hinokitiol in preventing renal fibrosis. Based on data from the GEO and Nephroseq databases, UHRF1 exhibited high expression levels in the unilateral ureteral obstruction (UUO) model and in patients with nephropathy. Gene set enrichment analysis predicted that UHRF1 may function through the TGF-β signaling pathway in fibrosis. By establishing a TGF-β1-stimulated HK2 cell model and animal models of renal fibrosis induced by UUO and folic acid, we confirmed that UHRF1 was highly expressed in both in vitro and in vivo models of renal fibrosis. After knockdown of UHRF1 in vitro, we found that the TGF-β/SMAD signaling pathway was inhibited, renal tubular epithelial cell EMT was reduced and renal fibrosis was attenuated. Hinokitiol has been reported to reduce the expression of UHRF1 mRNA and protein. We observed that inhibition of UHRF1 with Hinokitiol ameliorated induced EMT and renal fibrosis by reducing SMAD2/3 phosphorylation in vivo and in vitro. Taken together, our data demonstrated that the upregulation of UHRF1 accelerated the EMT of renal tubular cells and renal fibrosis through the TGF-β/SMAD signaling pathway. Hinokitiol may ameliorate renal fibrosis by suppressing the expression of UHRF1 in the kidney. |
| format | Article |
| id | doaj-art-a1a1ccbd0a5248a080ab30892663c7d1 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a1a1ccbd0a5248a080ab30892663c7d12025-02-02T12:16:25ZengNature PortfolioScientific Reports2045-23222025-01-0115111610.1038/s41598-025-86496-9UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathwayLijie Yang0Penghui Si1Tuoheti Kuerban2Linfa Guo3Shanzhi Zhan4Yisha Zuhaer5Yingtong Zuo6Peixiang Lu7Xiaojie Bai8Tongzu Liu9Department of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityDepartment of Urology, Zhongnan Hospital of Wuhan UniversityAbstract Renal fibrosis is widely recognized as the ultimate outcome of many chronic kidney diseases. The process of epithelial-mesenchymal transition (EMT) plays a critical role in the progression of fibrosis following renal injury. UHRF1, as a critical epigenetic regulator, may play an essential role in the pathogenesis and progression of renal fibrosis and EMT. However, the potential mechanisms remain to be elucidated. We aim to investigate the role of UHRF1 in EMT and renal fibrosis and to evaluate the potential benefits of Hinokitiol in preventing renal fibrosis. Based on data from the GEO and Nephroseq databases, UHRF1 exhibited high expression levels in the unilateral ureteral obstruction (UUO) model and in patients with nephropathy. Gene set enrichment analysis predicted that UHRF1 may function through the TGF-β signaling pathway in fibrosis. By establishing a TGF-β1-stimulated HK2 cell model and animal models of renal fibrosis induced by UUO and folic acid, we confirmed that UHRF1 was highly expressed in both in vitro and in vivo models of renal fibrosis. After knockdown of UHRF1 in vitro, we found that the TGF-β/SMAD signaling pathway was inhibited, renal tubular epithelial cell EMT was reduced and renal fibrosis was attenuated. Hinokitiol has been reported to reduce the expression of UHRF1 mRNA and protein. We observed that inhibition of UHRF1 with Hinokitiol ameliorated induced EMT and renal fibrosis by reducing SMAD2/3 phosphorylation in vivo and in vitro. Taken together, our data demonstrated that the upregulation of UHRF1 accelerated the EMT of renal tubular cells and renal fibrosis through the TGF-β/SMAD signaling pathway. Hinokitiol may ameliorate renal fibrosis by suppressing the expression of UHRF1 in the kidney.https://doi.org/10.1038/s41598-025-86496-9UHRF1Epithelial-mesenchymal transitionRenal fibrosisTGF-β/SMAD2/3 |
| spellingShingle | Lijie Yang Penghui Si Tuoheti Kuerban Linfa Guo Shanzhi Zhan Yisha Zuhaer Yingtong Zuo Peixiang Lu Xiaojie Bai Tongzu Liu UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway Scientific Reports UHRF1 Epithelial-mesenchymal transition Renal fibrosis TGF-β/SMAD2/3 |
| title | UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway |
| title_full | UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway |
| title_fullStr | UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway |
| title_full_unstemmed | UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway |
| title_short | UHRF1 promotes epithelial-mesenchymal transition mediating renal fibrosis by activating the TGF-β/SMAD signaling pathway |
| title_sort | uhrf1 promotes epithelial mesenchymal transition mediating renal fibrosis by activating the tgf β smad signaling pathway |
| topic | UHRF1 Epithelial-mesenchymal transition Renal fibrosis TGF-β/SMAD2/3 |
| url | https://doi.org/10.1038/s41598-025-86496-9 |
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