VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L
Abstract Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during t...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02045-x |
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| author | Qiuwen Wu Jiaxin Fu Bin Zhu Wei Meng Jingyi Ma Ying Lv Wenqi Zhao Fan Wang Jingjin Liu Yongshun Wang Cong Peng Shuo Zhang |
| author_facet | Qiuwen Wu Jiaxin Fu Bin Zhu Wei Meng Jingyi Ma Ying Lv Wenqi Zhao Fan Wang Jingjin Liu Yongshun Wang Cong Peng Shuo Zhang |
| author_sort | Qiuwen Wu |
| collection | DOAJ |
| description | Abstract Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury. |
| format | Article |
| id | doaj-art-088098f27a10483586ac4725babf43f7 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-088098f27a10483586ac4725babf43f72025-02-02T12:34:30ZengBMCCell Communication and Signaling1478-811X2025-01-0123112010.1186/s12964-025-02045-xVEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1LQiuwen Wu0Jiaxin Fu1Bin Zhu2Wei Meng3Jingyi Ma4Ying Lv5Wenqi Zhao6Fan Wang7Jingjin Liu8Yongshun Wang9Cong Peng10Shuo Zhang11Department of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Endocrinology and Diabetes, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)Department of Cardiology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)Department of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, the 2nd Affiliated Hospital of Harbin Medical UniversityAbstract Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.https://doi.org/10.1186/s12964-025-02045-xHypertensive nephropathyVEGFR3HSPA1LCrotonylationMitophagyOxidative stress |
| spellingShingle | Qiuwen Wu Jiaxin Fu Bin Zhu Wei Meng Jingyi Ma Ying Lv Wenqi Zhao Fan Wang Jingjin Liu Yongshun Wang Cong Peng Shuo Zhang VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L Cell Communication and Signaling Hypertensive nephropathy VEGFR3 HSPA1L Crotonylation Mitophagy Oxidative stress |
| title | VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L |
| title_full | VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L |
| title_fullStr | VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L |
| title_full_unstemmed | VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L |
| title_short | VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L |
| title_sort | vegfr3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of hspa1l |
| topic | Hypertensive nephropathy VEGFR3 HSPA1L Crotonylation Mitophagy Oxidative stress |
| url | https://doi.org/10.1186/s12964-025-02045-x |
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