Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway
Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway
复制标题
丁香树脂酚通过NRF2介导的抗氧化途径抑制细胞凋亡防治糖尿病肾病
DOI：
10.1007/s10565-023-09790-0
复制
发表时间：
2023-01-14
影响因子：
6.1
通讯作者：
Yang, Liang
中科院分区：
文献类型：
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作者：
Li, Guangru;Liu, Chang;Yang, Liang
糖尿病肾病是糖尿病的严重并发症之一，治疗选择有限。作为一种溶血性炎性细胞死亡，上睑下垂在糖尿病肾病的发病机制中起着重要作用。丁香酚(Syr)具有抗炎和抗氧化作用。然而，SyR对糖尿病肾病的治疗作用及其机制尚不清楚。在此，我们发现Syr治疗改善了链脲佐菌素(STZ)诱导的糖尿病小鼠的肾脏肥大、纤维化、系膜扩张、肾小球基底膜增厚和足细胞足突消失。从机制上讲，SyR可抑制炎性细胞因子IL-1β(IL-1β)和IL-18(IL-18)等炎症细胞因子的生物合成，从而抑制炎症相关蛋白如NLRP3、Caspase-1和Gasdermin D的表达。此外，SyR还促进了核因子E2相关因子2(NRF2)的核转位，并增强了下游抗氧化酶HO-1和MnSOD，从而有效地降低了过量活性氧(ROS)。最重要的是，NRF2基因敲除取消了SyR介导的NRF2-KO糖尿病小鼠的肾脏保护和抗炎活性。总体而言，Syr通过上调NRF2信号通路抑制糖尿病肾病NLRP3/Caspase-1/GSDMD松弛通路。这些发现表明，Syr可能是治疗糖尿病肾病的一种有前途的选择。
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 1 beta (IL-1 beta) 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.