GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy.
GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy.
复制标题
DOI：
10.1038/s41420-023-01452-8
复制
发表时间：
2023-05-11
影响因子：
7
通讯作者：
Shen, Yanna
中科院分区：
文献类型：
--
作者：
Li, Shengyu;Feng, Lifeng;Li, Guangru;Liu, Ruiqing;Ma, Changzhen;Wang, Lin;Gao, Aijiao;Liu, Chang;Cui, Yujie;Jiang, Zecheng;Xie, Yuhang;Wu, Qiang;Wang, Xia;Yang, Liang;Qi, Zhi;Shen, Yanna
糖尿病肾病（diabetic nephropathy，DN）是糖尿病严重的慢性微血管并发症之一，导致糖尿病患者的发病率和死亡率增高。Gasdermin E（GSDME）依赖的细胞凋亡信号通路在多种生理和病理过程中发挥重要作用。但其在DN中的作用及机制尚不清楚。本研究通过腹腔注射链脲佐菌素（STZ）成功建立了DN大鼠模型。STZ注射后第12周，肾组织结构和功能均出现异常，肾皮质caspase-3和GSDME蛋白水平表达明显上调。20周时，GSDME-N显著增加，同时伴有肾皮质caspase-1表达上调和血清中成熟IL-1β（mIL-1β）的释放。高糖条件下，HK 2和HBZY-1细胞中GSDME、caspase-3、caspase-1和IL-1β蛋白水平均升高。我们还发现，GSDME-N的表达显着下降时，caspase-3被敲低。相反，GSDME的敲低对胱天蛋白酶-3没有影响。有趣的是，caspase-3、caspase-1或GSDME敲低均减少mIL-1β的释放。最后，与野生型糖尿病大鼠相比，将腺相关病毒（AAV）9-shGSDME注射到大鼠肾脏中减少了肾损伤和肾细胞焦亡。这些结果表明，caspase-1的激活可诱导IL-1β成熟，caspase-3的激活可介导GSDME的裂解，从而导致质膜孔的形成和mIL-1β的胞浆释放。总之，我们确定了GSDME在DN中的促焦亡作用，这确实为临床治疗研究提供了重要依据。
Diabetic nephropathy (DN) is one of the serious chronic microvascular complications of diabetes, and leads to the increased morbidity and mortality in diabetic patients. Gasdermin E (GSDME)-dependent pyroptosis signaling pathway plays important roles in a variety of physiological and pathological processes. However, its role and mechanism in DN are still unclear. In this study, we established a rat DN model by intraperitoneal injection of streptozotocin (STZ) successfully. Structural and functional disorders in the kidney were exhibited on the 12th week after STZ injection; the expressions of caspase-3 and GSDME at protein level in renal cortex were significantly up-regulated. At the 20th week, GSDME-N increased significantly, accompanied by the upregulation of caspase-1 in renal cortex and the release of mature IL-1β (mIL-1β) in serum. Furthermore, we found the protein levels of GSDME, caspase-3, caspase-1 and IL-1β were all increased in HK2 and HBZY-1 cells under high-glucose conditions. We also found that the expression of GSDME-N significantly decreased when caspase-3 was knockdown. In contrast, knockdown of GSDME has no effect on caspase-3. Interestingly, either caspase-3, caspase-1 or GSDME knockdown reduced the release of mIL-1β. Finally, injection of adeno-associated virus (AAV) 9-shGSDME into the rat kidney reduced kidney damage and renal cell pyroptosis in comparison with wild-type diabetic rats. These results indicated that the activation of caspase-1 induced IL-1β maturation, and the activation of caspase-3 mediated cleavage of GSDME responsible for the formation of plasma membrane pore, followed by cytoplasmic release of mIL-1β. Overall, we identified a pro-pyroptosis role for GSDME in DN, which does provide an important basis for clinical therapeutic studies.
登录
查看更多内容
影响因子：
3.9
作者：
Hu Z;Lai Y;Ma C;Zuo L;Xiao G;Gao H;Xie B;Huang X;Gan H;Huang D;Yao N;Feng B;Ru J;Chen Y;Cai D
通讯作者：
Cai D
影响因子：
4.3
作者：
Chen X;Luo J;Wu M;Pan Z;Xie Y;Wang H;Chen B;Zhu H
通讯作者：
Zhu H
NLRP3/caspase-1/GSDMD™介导的细胞焦亡在抑郁小鼠模型的星形胶质细胞病理损伤中发挥关键作用
影响因子：
8
作者：
Li S;Sun Y;Song M;Song Y;Fang Y;Zhang Q;Li X;Song N;Ding J;Lu M;Hu G
通讯作者：
Hu G
影响因子：
2.5
作者：
Kelly, DJ;Stein-Oakley, A;Gilbert, RE
通讯作者：
Gilbert, RE
加油动物：凋亡的效应因子。
影响因子：
19
作者：
Kovacs SB;Miao EA
通讯作者：
Miao EA