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VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway

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Abstract

Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.

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Funding

This work was supported by Joint Guidance Project of Natural Science Foundation of Heilongjiang Province of China [LH2021H027] and Fund of Key Laboratory of Myocardial Ischemia, Ministry of Education [KF202222, KF201703]. Thanks to the staff of The Key Laboratory of Myocardial Ischemia for their help.

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  1. Qiuwen Wu, Wei Meng and Bin Zhu have authors contributed equally to this work.

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  1. Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China

    Qiuwen Wu, Wei Meng, Bin Zhu, Xi Chen, Jiaxin Fu, Chunyu Zhao, Gang Liu, Xing Luo, Ying Lv, Wenqi Zhao, Fan Wang, Sining Hu & Shuo Zhang

  2. The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150001, China

    Qiuwen Wu, Wei Meng, Bin Zhu, Xi Chen, Jiaxin Fu, Chunyu Zhao, Xing Luo, Ying Lv, Fan Wang, Sining Hu & Shuo Zhang

  3. National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150001, China

    Qiuwen Wu, Wei Meng, Bin Zhu, Sining Hu & Shuo Zhang

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Contributions

Qiuwen Wu, Sining Hu and Shuo Zhang conceived and designed the research; Qiuwen Wu, Xi Chen, Jiaxin Fu, Chunyu Zhao, Gang Liu and Wenqi Zhao performed the research and acquired the data; Wei Meng, Bin Zhu, Xing Luo, Ying Lv and Sining Hu analyzed and interpreted the data; Qiuwen Wu, Wei Meng and Bin Zhu drafted the original article and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sining Hu or Shuo Zhang.

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Wu, Q., Meng, W., Zhu, B. et al. VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway. Cell. Mol. Life Sci. 80, 327 (2023). https://doi.org/10.1007/s00018-023-04978-3

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  • DOI: https://doi.org/10.1007/s00018-023-04978-3

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