LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice
Abstract Background The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX is a copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of LOX in partial EMT and fibrotic progression in diabe...
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2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-06056-z |
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| author | Yicheng Lu Heyangzi Li Mohan Chen Yicheng Lin Xiaoming Zhang |
| author_facet | Yicheng Lu Heyangzi Li Mohan Chen Yicheng Lin Xiaoming Zhang |
| author_sort | Yicheng Lu |
| collection | DOAJ |
| description | Abstract Background The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX is a copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of LOX in partial EMT and fibrotic progression in diabetic nephropathy has not been investigated experimentally. Methods The bulk RNA sequencing and single-nuclei RNA sequencing (snRNA-seq) analysis were explored to find the role of LOX in diabetic nephropathy. We then investigated the partial EMT and the possible signaling pathway of LOX, both in vivo and in vitro by LOX inhibition experiments in diabetic mice and HK-2 cells. Besides, we further assessed kidney fibrosis and renal function. Results LOX expression was elevated in kidneys of diabetic mice. Additionally, snRNA-seq results indicated that LOX expression was higher in partial epithelial-mesenchymal transition proximal tubular (PemtPT) epithelial cells. Moreover, we found that increased LOX prompted partial EMT of renal tubular epithelial cells (RTECs) by modulating the transcription factor Snail both in vivo and in vitro. Remarkably, inhibition of LOX effectively mitigated the partial EMT of RTECs in diabetic mice, thereby attenuating kidney fibrosis and enhancing renal function. Additionally, we identified the TGF-β signaling pathway as an upstream regulator of LOX, and inhibiting LOX partially reversed the partial EMT program in HK-2 cells induced by the TGF-β signaling pathway. Conclusions Hyperglycemia induces partial EMT of RTECs via the TGF-β/LOX/Snail axis, thereby contributing to diabetic kidney fibrosis. Inhibiting LOX can effectively reverse the partial EMT of RTECs, diminish diabetic kidney fibrosis, and improve renal function. |
| format | Article |
| id | doaj-art-2ed0b7fa65f046d997d23e2534ee7e8d |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-2ed0b7fa65f046d997d23e2534ee7e8d2025-01-12T12:37:35ZengBMCJournal of Translational Medicine1479-58762025-01-0123111710.1186/s12967-024-06056-zLOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic miceYicheng Lu0Heyangzi Li1Mohan Chen2Yicheng Lin3Xiaoming Zhang4School of Medicine, Zhejiang UniversityDepartment of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang UniversitySchool of Life Sciences and Technology, Tongji UniversityXiangya School of Medicine, Central South UniversityDepartment of Basic Medical Sciences, The Second Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Background The partial epithelial-mesenchymal transition (EMT) is emerging as a significant mechanism in diabetic nephropathy (DN). LOX is a copper amine oxidase conventionally thought to act by crosslinking collagen. However, the role of LOX in partial EMT and fibrotic progression in diabetic nephropathy has not been investigated experimentally. Methods The bulk RNA sequencing and single-nuclei RNA sequencing (snRNA-seq) analysis were explored to find the role of LOX in diabetic nephropathy. We then investigated the partial EMT and the possible signaling pathway of LOX, both in vivo and in vitro by LOX inhibition experiments in diabetic mice and HK-2 cells. Besides, we further assessed kidney fibrosis and renal function. Results LOX expression was elevated in kidneys of diabetic mice. Additionally, snRNA-seq results indicated that LOX expression was higher in partial epithelial-mesenchymal transition proximal tubular (PemtPT) epithelial cells. Moreover, we found that increased LOX prompted partial EMT of renal tubular epithelial cells (RTECs) by modulating the transcription factor Snail both in vivo and in vitro. Remarkably, inhibition of LOX effectively mitigated the partial EMT of RTECs in diabetic mice, thereby attenuating kidney fibrosis and enhancing renal function. Additionally, we identified the TGF-β signaling pathway as an upstream regulator of LOX, and inhibiting LOX partially reversed the partial EMT program in HK-2 cells induced by the TGF-β signaling pathway. Conclusions Hyperglycemia induces partial EMT of RTECs via the TGF-β/LOX/Snail axis, thereby contributing to diabetic kidney fibrosis. Inhibiting LOX can effectively reverse the partial EMT of RTECs, diminish diabetic kidney fibrosis, and improve renal function.https://doi.org/10.1186/s12967-024-06056-zLysyl oxidaseSingle-nuclei RNA sequencingDiabetic nephropathyPartial epithelial-mesenchymal transitionTubulointerstitial fibrosis |
| spellingShingle | Yicheng Lu Heyangzi Li Mohan Chen Yicheng Lin Xiaoming Zhang LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice Journal of Translational Medicine Lysyl oxidase Single-nuclei RNA sequencing Diabetic nephropathy Partial epithelial-mesenchymal transition Tubulointerstitial fibrosis |
| title | LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice |
| title_full | LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice |
| title_fullStr | LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice |
| title_full_unstemmed | LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice |
| title_short | LOX-induced tubulointerstitial fibrosis via the TGF-β/LOX/Snail axis in diabetic mice |
| title_sort | lox induced tubulointerstitial fibrosis via the tgf β lox snail axis in diabetic mice |
| topic | Lysyl oxidase Single-nuclei RNA sequencing Diabetic nephropathy Partial epithelial-mesenchymal transition Tubulointerstitial fibrosis |
| url | https://doi.org/10.1186/s12967-024-06056-z |
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