Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; Department of Neuroscience Research Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Department of Neuroscience Research Center, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
Biochim Biophys Acta Mol Cell Res. 2024 Apr;1871(4):119703. doi: 10.1016/j.bbamcr.2024.119703. Epub 2024 Mar 5.
Imidazole propionate (ImP) is a detrimental metabolite produced by the fermentation of histidine intermediates via the intestinal flora. Here, the untargeted metabolite analysis of plasma metabolites from patients with diabetic nephropathy (DN), in combination with the Human Metabolome Database, revealed significantly increased levels of ImP in patients with DN, with a positive correlation with patients' blood creatinine concentration and urinary albumin-to-creatinine ratio, and a negative correlation with the glomerular filtration rate. RNA-seq was applied to detect the effects of ImP on renal tissue transcriptome in mice with DN. It demonstrated that ImP exacerbated renal injury in mice with DN and promoted renal tubular epithelial-mesenchymal transition (EMT), leading to renal mesenchymal fibrosis and renal impairment. Furthermore, ImP was found to directly target HAP90α and activate the PI3K-Akt signalling pathway, which is involved in EMT, by the drug affinity response target stability method. The findings showed that ImP may provide a novel target for DN quality, as it can directly bind to and activate HSP90, thereby facilitating the development of DN while acting as a potential indicator for the clinical diagnosis of DN.
咪唑丙酸（ImP）是一种有害代谢物，由肠道菌群通过组氨酸中间体发酵产生。在这里，对糖尿病肾病（DN）患者血浆代谢物的非靶向代谢物分析，结合人类代谢组数据库，发现 DN 患者的 ImP 水平显著升高，与患者的血肌酐浓度和尿白蛋白与肌酐比值呈正相关，与肾小球滤过率呈负相关。RNA-seq 被应用于检测 ImP 对糖尿病肾病小鼠肾组织转录组的影响。结果表明，ImP 加剧了糖尿病肾病小鼠的肾损伤，并促进了肾小管上皮-间充质转化（EMT），导致肾间质纤维化和肾功能损害。此外，通过药物亲和反应靶标稳定性方法发现，ImP 直接靶向 HAP90α 并激活参与 EMT 的 PI3K-Akt 信号通路。这些发现表明，ImP 可能为糖尿病肾病的治疗提供一个新的靶点，因为它可以直接结合并激活 HSP90，从而促进糖尿病肾病的发展，同时作为糖尿病肾病临床诊断的一个潜在指标。
