Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.
The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
Exp Clin Endocrinol Diabetes. 2020 Sep;128(9):599-606. doi: 10.1055/a-1069-7290. Epub 2020 Jan 20.
The inflammation of glomerular endothelial cells induces and promotes the activation of macrophages and contributes to the development of diabetic nephropathy. Thus, this study aimed to investigate the gene regulatory effect and potential role of pyruvate kinase M2 (PKM2) in inflammatory response in diabetic nephropathy.
The plasma PKM2 levels of patients with diabetes were evaluated. Eight-week-old mice were divided into three groups (WT, db/db mice, and db/db mice treated with TEPP-46) and raised for 12 weeks. Blood and kidney samples were collected at the end of the experiment. Endothelial cells were stimulated with high glucose with or without TEPP-46. The expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), phospho-PKM2, PKM2, phospho-STAT3(signal transducer and activator of transcription), STAT3, nuclear factor kappa B (NF-kB), and phospho-NF-kB and were determined using Western blot. The activation of macrophages (CD68CD86) in the glomeruli was assessed via fluorescent double staining. Moreover, immune endothelial adhesion experiments were performed.
The plasma PKM2 levels of patients with type 2 diabetes increased. P-PKM2 was up-regulated and . TEPP-46 decreased inflammatory cell infiltration and ICAM-1 expression and and inhibited the differentiation of macrophages to M1 cells in db/db mice with diabetic nephropathy. PKM2 regulated the phosphorylation of STAT3 and NF-kB. Furthermore, high glucose levels induced the transition from tetramer to dimer and the nuclear translocation of PKM2.
The gene regulatory effect of PKM2 is involved in renal inflammation in type 2 diabetic nephropathy by promoting the phosphorylation of STAT3 and NF-kB and the expression of intercellular adhesion molecule 1. Thus, the down-regulation of phosphorylated PKM2 may have protective effects against diabetic nephropathy by inhibiting renal inflammation.
肾小球内皮细胞的炎症诱导并促进巨噬细胞的激活，并促进糖尿病肾病的发展。因此，本研究旨在探讨丙酮酸激酶 M2（PKM2）在糖尿病肾病炎症反应中的基因调控作用及潜在作用。
评估了糖尿病患者的血浆 PKM2 水平。将 8 周龄的小鼠分为三组（WT、db/db 小鼠和 db/db 小鼠用 TEPP-46 治疗）并饲养 12 周。实验结束时采集血液和肾脏样本。用高糖刺激内皮细胞，有或无 TEPP-46。使用 Western blot 检测细胞间黏附分子 1（ICAM-1）、白细胞介素 6（IL-6）、白细胞介素 1β（IL-1β）、磷酸化 PKM2、PKM2、磷酸化信号转导和转录激活因子 3（STAT3）、STAT3、核因子 kappa B（NF-kB）和磷酸化 NF-kB 的表达。通过荧光双重染色评估肾小球中巨噬细胞（CD68CD86）的激活。此外，还进行了免疫内皮细胞黏附实验。
2 型糖尿病患者的血浆 PKM2 水平升高。PKM2 被上调，且。TEPP-46 降低了糖尿病肾病 db/db 小鼠的炎症细胞浸润和 ICAM-1 的表达，并抑制了巨噬细胞向 M1 细胞的分化。PKM2 调节 STAT3 和 NF-kB 的磷酸化。此外，高糖水平诱导 PKM2 从四聚体向二聚体转变，并促进其核转位。
PKM2 的基因调控作用通过促进 STAT3 和 NF-kB 的磷酸化以及细胞间黏附分子 1 的表达，参与 2 型糖尿病肾病的肾脏炎症反应。因此，抑制磷酸化 PKM2 的下调可能通过抑制肾脏炎症对糖尿病肾病具有保护作用。
