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）以代谢谱异常为特征。代谢组学研究显示，糖尿病肾病患者的血清3-磷酸甘油酸（3-phosphoglycerate, 3-PG）水平升高。作为3-PG合成的关键限速酶，磷酸甘油酸激酶1（phosphoglycerate kinase 1, PGK1）的蛋白表达在糖尿病肾病患者及模型小鼠中均同步上调。肾小管上皮细胞特异性敲除PGK1可显著缓解糖尿病肾病的进展，而PGK1过表达则会显著加重病情。机制层面，PGK1依赖的酶促3-PG生成通过抑制谷胱甘肽过氧化物酶1（GPX1）以激活NLRP3炎症小体（NLRP3 inflammasome），进而促进糖尿病肾病的发生发展。此外，PGK1还可通过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）依赖的炎症反应。转录因子配对盒蛋白5（paired box protein 5, PAX5）可介导糖尿病肾病中PGK1的表达上调。高通量筛选结果显示，ChemDiv库中的C-16、天然产物利里尼丁（lirinidine）以及美国食品药品监督管理局（FDA）批准的奥克太尔双羟萘酸盐（Oxantel Pamoate）均为强效PGK1拮抗剂，可有效预防糖尿病肾病。综上，阻断PGK1或是糖尿病肾病临床管理的极具潜力的新策略。本研究已将原始印迹膜（未校正、未裁剪且带有分子量标志物）及细胞原始染色图像上传至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）中的作用机制研究，通过酶依赖性和非酶依赖性途径揭示PGK1如何促进疾病发展。数据集包含原始实验数据，如未调整的Western Blot印迹和细胞染色图像，以支持研究结论。数据来自江南大学，采用Western Blot和染色技术，并遵循CC BY 4.0开放许可，便于学术共享和再利用。