Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model
Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune-complex deposits and inflammatory cell infiltrations in multiple organs. Approximately half of lupus patients have nephritis. Lymphangiogenesis is the proliferation of lymphatic vessels (LVs), which r...
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02624-4 |
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| author | Tian Wang Wenjia Li Ji-Hyun Yeom Zhiheng Liu Kyoung Min Kim Kyung Pyo Kang |
| author_facet | Tian Wang Wenjia Li Ji-Hyun Yeom Zhiheng Liu Kyoung Min Kim Kyung Pyo Kang |
| author_sort | Tian Wang |
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| description | Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune-complex deposits and inflammatory cell infiltrations in multiple organs. Approximately half of lupus patients have nephritis. Lymphangiogenesis is the proliferation of lymphatic vessels (LVs), which regulate tissue fluid homeostasis and immune cell trafficking, responding to the tissue environment. In this study, we evaluated the therapeutic effect of SAR131675, a selective VEGFR-3 inhibitor, on the murine lupus nephritis model by regulating inflammation and lymphangiogenesis. We evaluated biopsy-proven lupus nephritis with immunohistochemical staining for D2-40, a marker for human lymphatic endothelial cells. For animal experiments, 7- to 8-week-old male BALB/c mice were used. For the induction of a lupus-like model, the dorsal skin of mice was shaved and given topical treatment every other day with 100 μg resiquimod dissolved in 100 μL acetone during the 8-week treatment. We had renal histology and immunofluorescent study for inflammatory cells and lymphatic vessels. We also had a qRT-PCR and Western blot analysis to evaluate inflammatory cytokines and chemokines, lymphangiogenic factors, and TLR7/type I IFN response. A human study found that the higher the revised ISN/RPS LN histopathological classification and modified NIH activity indexes, the more D2-40 (+) lymphatic vessels were expressed in the tubulointerstitial areas. Inhibition of VEGFR-3 by oral SAR131675 treatment decreased the resiquimod-induced glomerular and tubulointerstitial inflammation and attenuated LYVE-1 (+) lymphatic vessel expression in the murine lupus model. Treatment SAR131675 decreased the resiquimod-induced increase of proinflammatory cytokines and chemokines by regulating TLR7/MyD88/IFN-α expression. This study suggests the therapeutic potential of targeting lymphatic proliferation by VEGFR-3 inhibition in lupus nephritis. Modulation of the lymphatic network may provide a novel approach to treating chronic inflammation and attenuating renal autoimmune response. |
| format | Article |
| id | doaj-art-e3ae00ab7b424539ba043d3cce9eb632 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-e3ae00ab7b424539ba043d3cce9eb6322025-08-20T03:04:22ZengNature Publishing GroupCell Death Discovery2058-77162025-07-0111111310.1038/s41420-025-02624-4Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis modelTian Wang0Wenjia Li1Ji-Hyun Yeom2Zhiheng Liu3Kyoung Min Kim4Kyung Pyo Kang5Department of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical SchoolDepartment of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical SchoolDepartment of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical SchoolDepartment of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical SchoolDepartment of Pathology, Jeonbuk National University Medical SchoolDepartment of Internal Medicine, Research Institute of Clinical Medicine, Jeonbuk National University Medical SchoolAbstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune-complex deposits and inflammatory cell infiltrations in multiple organs. Approximately half of lupus patients have nephritis. Lymphangiogenesis is the proliferation of lymphatic vessels (LVs), which regulate tissue fluid homeostasis and immune cell trafficking, responding to the tissue environment. In this study, we evaluated the therapeutic effect of SAR131675, a selective VEGFR-3 inhibitor, on the murine lupus nephritis model by regulating inflammation and lymphangiogenesis. We evaluated biopsy-proven lupus nephritis with immunohistochemical staining for D2-40, a marker for human lymphatic endothelial cells. For animal experiments, 7- to 8-week-old male BALB/c mice were used. For the induction of a lupus-like model, the dorsal skin of mice was shaved and given topical treatment every other day with 100 μg resiquimod dissolved in 100 μL acetone during the 8-week treatment. We had renal histology and immunofluorescent study for inflammatory cells and lymphatic vessels. We also had a qRT-PCR and Western blot analysis to evaluate inflammatory cytokines and chemokines, lymphangiogenic factors, and TLR7/type I IFN response. A human study found that the higher the revised ISN/RPS LN histopathological classification and modified NIH activity indexes, the more D2-40 (+) lymphatic vessels were expressed in the tubulointerstitial areas. Inhibition of VEGFR-3 by oral SAR131675 treatment decreased the resiquimod-induced glomerular and tubulointerstitial inflammation and attenuated LYVE-1 (+) lymphatic vessel expression in the murine lupus model. Treatment SAR131675 decreased the resiquimod-induced increase of proinflammatory cytokines and chemokines by regulating TLR7/MyD88/IFN-α expression. This study suggests the therapeutic potential of targeting lymphatic proliferation by VEGFR-3 inhibition in lupus nephritis. Modulation of the lymphatic network may provide a novel approach to treating chronic inflammation and attenuating renal autoimmune response.https://doi.org/10.1038/s41420-025-02624-4 |
| spellingShingle | Tian Wang Wenjia Li Ji-Hyun Yeom Zhiheng Liu Kyoung Min Kim Kyung Pyo Kang Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model Cell Death Discovery |
| title | Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| title_full | Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| title_fullStr | Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| title_full_unstemmed | Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| title_short | Inhibition of VEGFR-3 by SAR131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| title_sort | inhibition of vegfr 3 by sar131675 decreases renal inflammation and lymphangiogenesis in the murine lupus nephritis model |
| url | https://doi.org/10.1038/s41420-025-02624-4 |
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