Yong Wei, Li Ziyi, Xu Weilong, Gao Danni, Sha Baixue, Jin Yinuo, Shen Yumeng, Zhang Yanfeng, Pan Yi, Liu Jianxing, Zhang Fangfang, Yu Jiangyi, Jin Liang, Yang Yue
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
School of Medicine & Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
Phytomedicine. 2025 Nov;147:157213. doi: 10.1016/j.phymed.2025.157213. Epub 2025 Aug 27.
Diabetic kidney disease (DKD) represents a common microvascular complication associated with diabetes. Research suggests that lipid accumulation contributes to lipotoxicity, exacerbating kidney injury in DKD. Quercetin (QCT), a flavonoid derived from specific fruits and vegetables, has shown potential in mitigating DKD progression; however, its precise protective mechanisms remain to be explored.
This study aimed to explore the effects of quercetin (QCT) on lipid accumulation in DKD and elucidate the underlying mechanisms.
The pathological and molecular changes associated with DKD were examined through histological, biochemical, and transcriptomic analyses in DKD mice and cell models treated with QCT. Bioinformatics analysis was conducted to identify key targets of QCT in DKD treatment. Molecular docking, cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were utilized to confirm the interaction of QCT and the identified targets. Moreover, PPARA/PPARG inhibitors and si-UCP1 were co-incubated with QCT in DKD cell models to assess their regulatory roles.
QCT significantly improved renal function, reduced lipid deposition, and mitigated renal fibrosis in DKD mice. Peroxisome proliferator-activated receptors alpha and gamma (PPARA and PPARG) were identified as critical targets of QCT in DKD treatment. Inhibition of PPARA and PPARG in HK-2 cells reduced the protective effects of QCT. Transcriptomic analysis revealed that QCT activated the PPARA/PPARG-UCP1 axis, enhancing fatty acid oxidation, decreasing reactive oxygen species (ROS) production, and alleviating lipotoxicity.
QCT ameliorated renal injury in DKD by improving lipid accumulation via the PPARA/PPARG-UCP1 axis, highlighting its potential as a therapeutic option for DKD treatment.
糖尿病肾病（DKD）是糖尿病常见的微血管并发症。研究表明，脂质蓄积会导致脂毒性，加重DKD中的肾损伤。槲皮素（QCT）是一种源自特定水果和蔬菜的黄酮类化合物，已显示出减轻DKD进展的潜力；然而，其确切的保护机制仍有待探索。
本研究旨在探讨槲皮素（QCT）对DKD中脂质蓄积的影响，并阐明其潜在机制。
通过组织学、生化和转录组分析，在接受QCT治疗的DKD小鼠和细胞模型中检测与DKD相关的病理和分子变化。进行生物信息学分析以确定QCT在DKD治疗中的关键靶点。利用分子对接、细胞热位移分析（CETSA）和表面等离子体共振（SPR）来确认QCT与所鉴定靶点的相互作用。此外，将PPARA/PPARG抑制剂和si-UCP1与QCT在DKD细胞模型中共孵育，以评估它们的调节作用。
QCT显著改善了DKD小鼠的肾功能，减少了脂质沉积，并减轻了肾纤维化。过氧化物酶体增殖物激活受体α和γ（PPARA和PPARG）被确定为QCT在DKD治疗中的关键靶点。在HK-2细胞中抑制PPARA和PPARG可降低QCT的保护作用。转录组分析显示，QCT激活了PPARA/PPARG-UCP1轴，增强了脂肪酸氧化，减少了活性氧（ROS）的产生，并减轻了脂毒性。
QCT通过PPARA/PPARG-UCP1轴改善脂质蓄积，从而改善DKD中的肾损伤，突出了其作为DKD治疗的一种治疗选择的潜力。
