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Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway

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Abstract

Diabetic nephropathy (DN) is one of the serious complications of diabetes that has limited treatment options. As a lytic inflammatory cell death, pyroptosis plays an important role in the pathogenesis of DN. Syringaresinol (SYR) possesses anti-inflammatory and antioxidant properties. However, the therapeutic effects and the underlying mechanism of SYR in DN remain unclear. Herein, we showed that SYR treatment ameliorated renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, and podocyte foot process effacement in streptozotocin (STZ)-induced diabetic mice. Mechanistically, SYR prevented the abundance of pyroptosis-related proteins such as NOD-like receptor family pyrin domain containing 3 (NLRP3), cysteinyl aspartate-specific proteinase 1 (Caspase-1), and gasdermin D (GSDMD), and the biosynthesis of inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). In addition, SYR promoted the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) and enhanced the downstream antioxidant enzymes heme oxygenase 1 (HO-1) and manganese superoxide dismutase (MnSOD), thereby effectively decreasing excess reactive oxygen species (ROS). Most importantly, knockout of NRF2 abolished SYR-mediated renoprotection and anti-pyroptotic activities in NRF2-KO diabetic mice. Collectively, SYR inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway by upregulating NRF2 signaling in DN. These findings suggested that SYR may be promising a therapeutic option for DN.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82172170, 81971887, 31971194, and 82072187); the Natural Science Foundation of Tianjin (Nos. 20JCYBJC01260, 20JCYBJC01230, and 20JCQNJC01850); Tianjin Key Medical Discipline (Specialty) Construction Project; Key Laboratory of Emergency and Trauma (Hainan Medical University), Ministry of Education (No. KLET-202018 and KLET-201906); and Fundamental Research Funds for the Central Universities (No. 63211140).

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Conception and study design: Liang Yang, Zhi Qi, and Guangru Li. Animal model and sample collection: Lei Yang and Lifeng Feng. Data acquisition from animal samples: Guangru Li and Jiale An. Cell experiments and relevant data acquisition: Chang Liu and Shengzheng Zhang. Data analysis: Jing Li, Yang Gao, Zhongjie Pan, Yang Xu, Jie Liu, Yachen Wang, Jie Yan, and Jianlin Cui. Manuscript drafting: Guangru Li. Manuscript revising: Zhi Qi and Liang Yang. All authors approved the final version of the manuscript.

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Correspondence to Zhi Qi or Liang Yang.

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All animal care and experimental procedures were approved by the Institute Research Ethics Committee of Nankai University (permit number: 10011) and strictly conformed to the Guide for the Care and Use of Laboratory Animals of Nankai University.

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The authors declare no competing interests.

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Li, G., Liu, C., Yang, L. et al. Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway. Cell Biol Toxicol 39, 621–639 (2023). https://doi.org/10.1007/s10565-023-09790-0

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  • DOI: https://doi.org/10.1007/s10565-023-09790-0

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