Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao; Luzhou Key Laboratory of Cardiovascular and Metabolic Diseases, Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China.
Luzhou Key Laboratory of Cardiovascular and Metabolic Diseases, Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, PR China.
Int Immunopharmacol. 2019 Oct;75:105832. doi: 10.1016/j.intimp.2019.105832. Epub 2019 Aug 29.
We recently found that Sodium butyrate (NaB) possesses anti-inflammatory effects in diabetic nephropathy (DN) mouse model and in high-glucose induced mouse glomerular mesangial cells. Pyroptosis is a programmed cell death accompanied with the release of pro-inflammatory factors. Gasdermin D (GSDMD) is a novel discovered pivotal executive protein of pyroptosis, which can be cleaved by inflammatory caspases. The aim of our study is to verify if NaB have some effects against high-glucose induces pyroptosis in renal Glomerular endothelial cells (GECs). For this aim, human GECs were cultured and exposed to high-glucose. Exogenous NaB, caspase 1 inhibitor Ac-YVAD-CMK (A-Y-C) or knockdown GSDMD by siRNA were used. We found high glucose could increase Propidium Iodide (PI) positive cells and elevate release of lactate dehydrogenase (LDH), Interleukin 1 beta (IL-1β) and Interleukin 18 (IL-18); protein levels of GSDMD, GSDMD N-terminal domain (GSDMD-N) and cleaved-caspase-1 were also elevated. Effect of NaB on LDH release and PI positive cells was further enhanced by inhibiting caspase 1-GSDMD. In addition, high glucose-induced nuclear factor kappa-B (NF-κB)/NF-κB inhibitor α (IκB-α) signaling pathway was reversed by NaB or A-Y-C administration. In conclusion, NaB could ameliorate high-glucose induced GECs via caspase1-GSDMD canonical pyroptosis pathway; and NF-κB/IκB-α signaling pathway was involved in it.
我们最近发现丁酸钠（NaB）在糖尿病肾病（DN）小鼠模型和高糖诱导的小鼠肾小球系膜细胞中具有抗炎作用。细胞焦亡是一种伴有促炎因子释放的程序性细胞死亡。Gasdermin D（GSDMD）是一种新发现的细胞焦亡的关键执行蛋白，它可以被炎性半胱天冬酶切割。我们研究的目的是验证 NaB 是否对高糖诱导的肾小球内皮细胞（GEC）中的细胞焦亡有一定的作用。为此，我们培养人 GEC 并使其暴露于高糖中。使用外源性 NaB、半胱天冬酶 1 抑制剂 Ac-YVAD-CMK（A-Y-C）或 siRNA 敲低 GSDMD。我们发现高葡萄糖可增加碘化丙啶（PI）阳性细胞数，并增加乳酸脱氢酶（LDH）、白细胞介素 1β（IL-1β）和白细胞介素 18（IL-18）的释放；GSDMD、GSDMD N 端结构域（GSDMD-N）和裂解的半胱天冬酶 1 的蛋白水平也升高。抑制半胱天冬酶 1-GSDMD 进一步增强了 NaB 对 LDH 释放和 PI 阳性细胞的作用。此外，高葡萄糖诱导的核因子 kappa-B（NF-κB）/NF-κB 抑制剂α（IκB-α）信号通路被 NaB 或 A-Y-C 处理逆转。总之，NaB 可以通过半胱天冬酶 1-GSDMD 经典细胞焦亡途径改善高糖诱导的 GEC 损伤，NF-κB/IκB-α 信号通路参与其中。
