Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners

Diabetic kidney disease (DKD) is characterized by abnormal metabolic profiles. Metabolomics revealed increased serum levels of 3-phosphoglycerate (3-PG) in DKD patients. The protein expression of phosphoglycerate kinase 1 (PGK1), a key rate-limiting enzyme for 3-PG synthesis, was concomitantly upregulated in DKD patients and mice. The development of DKD was significantly mitigated by renal tubular epithelial cell-specific knockout of PGK1 and robustly worsened by PGK1 overexpression. Mechanistically, PGK1-dependent enzymatic production of 3-PG facilitated DKD through inhibiting GPX1 to activate the NLRP3 inflammasome. PGK1 promoted UNC5CL-mediated inflammation by binding with aldehyde dehydrogenase-1 L1 (Aldh1l1) through its non-enzymatic activity. The transcription factor paired box protein 5 (PAX5) mediated the upregulation of PGK1 in DKD. High-throughput screening revealed that C-16 from ChemDiv, the natural product lirinidine, and the FDA-approved Oxantel Pamoate were potent PGK1 antagonists and efficaciously prevented DKD. Overall, blocking PGK1 may be a promising avenue for DKD management. Here, we had put the raw blots (unadjusted and uncropped blots with size markers) and raw stained images for cells in Mendeley.

糖尿病肾病（Diabetic kidney disease, DKD）以代谢谱异常为核心特征。代谢组学分析显示，DKD患者血清内3-磷酸甘油酸(3-phosphoglycerate, 3-PG)水平显著升高。作为3-PG合成的关键限速酶，磷酸甘油酸激酶1(phosphoglycerate kinase 1, PGK1)的蛋白表达在DKD患者与小鼠模型中均同步上调。特异性敲除肾小管上皮细胞中的PGK1可显著延缓DKD的疾病进展，而PGK1过表达则会显著加重DKD的病情。机制层面研究表明，PGK1通过酶促反应生成的3-PG可通过抑制谷胱甘肽过氧化物酶1(Glutathione Peroxidase 1, GPX1)以激活NLRP3炎症小体(NLRP3 inflammasome)，进而促进DKD的发生发展。此外，PGK1还可借助其非酶促活性与醛脱氢酶1L1(aldehyde dehydrogenase-1 L1, Aldh1l1)结合，介导UNC5C样蛋白(UNC5CL)依赖的炎症应答。转录因子配对盒蛋白5(paired box protein 5, PAX5)可介导DKD中PGK1的上调表达。高通量筛选结果显示，ChemDiv公司的C-16化合物、天然产物利里尼定(lirinidine)以及美国食品药品监督管理局(FDA)批准的双羟萘酸奥克太尔(Oxantel Pamoate)均为强效PGK1拮抗剂，可有效预防DKD。综上，靶向阻断PGK1或可成为DKD临床管理的极具潜力的新策略。本研究已将原始蛋白印迹膜（未校正、未裁剪且带有分子量标记）及细胞染色原始图像上传至Mendeley平台。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于磷酸甘油酸激酶1（PGK1）在糖尿病肾病（DKD）中的双重作用机制，通过酶依赖和非酶依赖方式促进疾病发展，并包含原始实验数据如Western Blot和细胞染色图像。研究发现PGK1通过产生3-磷酸甘油酸激活炎症通路，同时与非酶活性结合介导炎症，且筛选出潜在PGK1拮抗剂，为DKD治疗提供新靶点。数据来自江南大学，采用CC BY 4.0许可证，支持开放共享。