木犀草素通过AMPK/NLRP3/TGF-β信号通路减轻糖尿病肾病纤维化

Luteolin Alleviates Diabetic Nephropathy Fibrosis Involving AMPK/NLRP3/TGF-β Pathway.

作者信息

Huang Rong, Zeng Jun, Yu Xiaoze, Shi Yunke, Song Na, Zhang Jie, Wang Peng, Luo Min, Ma Yiming, Xiao Chuang, Wang Lueli, Du Guanhua, Cai Hongyan, Yang Weimin

机构信息

School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, People's Republic of China.

The First Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.

出版信息

Diabetes Metab Syndr Obes. 2024 Jul 30;17:2855-2867. doi: 10.2147/DMSO.S450094. eCollection 2024.

PURPOSE

Luteolin is a promising candidate for diabetic nephropathy due to its potential anti-inflammatory and anti-fibrotic properties. This study explored the molecular mechanisms through which luteolin combats fibrosis in DN.

METHODS

Potential targets affected by luteolin and genes associated with DN were collected from databases. Overlapping targets between luteolin and diabetic nephropathy were identified through Venn analysis. A protein-protein interaction network was constructed using these common targets, and critical pathways and targets were elucidated through GO and KEGG analysis. These pathways and targets were confirmed using a streptozotocin-induced mouse model. Luteolin was administered at 45 mg/kg and 90 mg/kg. Various parameters were evaluated, including body weight, blood glucose levels, and histopathological examinations. Protein levels related to energy metabolism, inflammation, and fibrosis were quantified.

RESULTS

Fifty-three targets associated with luteolin and 36 genes related to diabetic nephropathy were extracted. The AGE-RAGE signaling pathway was the key pathway impacted by luteolin in diabetic nephropathy. Key molecular targets include TGF-β, IL-1β, and PPARG. Luteolin reduced body weight and blood glucose levels, lowered the left kidney index, and improved insulin and glucose tolerance. Furthermore, luteolin mitigated inflammatory cell infiltration, basement membrane thickening, and collagen deposition in the kidney. Luteolin up-regulated the protein expression of p-AMPKα (Th172) while simultaneously down-regulated the protein expression of p-NF-ĸB (p65), NLRP3, TGF-β1, α-SMA, and Collagen I.

CONCLUSION

Luteolin mitigated renal fibrosis by alleviating energy metabolism disruptions and inflammation by modulating the AMPK/NLRP3/TGF-β signaling pathway.

目的

木犀草素因其潜在的抗炎和抗纤维化特性，有望成为治疗糖尿病肾病的候选药物。本研究探讨了木犀草素对抗糖尿病肾病纤维化的分子机制。

方法

从数据库中收集受木犀草素影响的潜在靶点和与糖尿病肾病相关的基因。通过维恩分析确定木犀草素与糖尿病肾病之间的重叠靶点。利用这些共同靶点构建蛋白质-蛋白质相互作用网络，并通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析阐明关键途径和靶点。使用链脲佐菌素诱导的小鼠模型对这些途径和靶点进行验证。给予小鼠45mg/kg和90mg/kg的木犀草素。评估各种参数，包括体重、血糖水平和组织病理学检查。对与能量代谢、炎症和纤维化相关的蛋白质水平进行定量分析。

结果

提取了53个与木犀草素相关的靶点和36个与糖尿病肾病相关的基因。晚期糖基化终末产物-晚期糖基化终末产物受体（AGE-RAGE）信号通路是木犀草素在糖尿病肾病中影响的关键通路。关键分子靶点包括转化生长因子-β（TGF-β）、白细胞介素-1β（IL-1β）和过氧化物酶体增殖物激活受体γ（PPARG）。木犀草素降低了体重和血糖水平，降低了左肾指数，并改善了胰岛素和葡萄糖耐受性。此外，木犀草素减轻了肾脏中的炎性细胞浸润、基底膜增厚和胶原沉积。木犀草素上调了磷酸化腺苷酸活化蛋白激酶α（p-AMPKα，Thr172）的蛋白表达，同时下调了磷酸化核因子-κB（p-NF-κB，p65）、NLR家族含pyrin结构域蛋白3（NLRP3）、TGF-β1、α-平滑肌肌动蛋白（α-SMA）和胶原蛋白I的蛋白表达。