牛蒡子通过Apoh/PPAR-γ通路减轻糖尿病肾病。

Fructus arctii mitigates diabetic nephropathy via the Apoh/PPAR-γ pathway.

作者信息

Zhang Na, Chen Anhui, Dong Yuwei, Dou Deqiang

机构信息

School of Food and Biological Engineering, Xuzhou University of Technology, Xuzhou, Jiangsu 221018, China.

出版信息

Mol Immunol. 2025 May;181:18-28. doi: 10.1016/j.molimm.2025.02.017. Epub 2025 Mar 7.

DOI:10.1016/j.molimm.2025.02.017

PMID:40056629

Abstract

BACKGROUND

Diabetic nephropathy (DN) is characterized by renal fibrosis and functional decline. Apolipoprotein H (Apoh) and Fructus arctii, a traditional medicinal plant, have demonstrated potential in treating metabolic and fibrotic disorders. This study Focused on revealing the roles of Apoh and Fructus arctii in mitigating DN.

METHODS

Db/db mice served as an in vivo DN model, and mouse glomerular mesangial cells (mMCs) and renal tubular epithelial cells (mTECs) were treated with high glucose (HG) to simulate DN in vitro. Apoh silencing and overexpression were performed using shRNA and pcDNA3.1 vectors. Fructus arctii was administered to both cellular and animal models to assess its therapeutic potential. Cellular proliferation was measured using CCK-8 and EdU assays, while fibrosis markers were analyzed by Western blot, IHC and RT-qPCR. PPAR-γ pathway involvement was confirmed through treatment with the antagonist GW9662. Renal structural changes were evaluated with histological staining including H&E, PAS, Masson's trichrome, and picrosirius red staining.

RESULTS

Apoh expression was markedly reduced in HG-treated cells and the kidneys of db/db mice. Overexpression of Apoh suppressed HG-induced proliferation in mMCs and mTECs by downregulating cyclin D1 and PCNA. Additionally, Apoh overexpression alleviated fibrosis by reducing Fibronectin, Collagen I, and α-SMA levels, effects mediated through the PPAR-γ pathway. Treatment with the PPAR-γ antagonist GW9662 reversed these protective effects. In db/db mice, Fructus arctii administration improved renal function by reducing blood glucose, proteinuria, and renal collagen deposition. It also alleviated fibrosis and enhanced Apoh and PPAR-γ expression. Silencing Apoh nullified the protective effects of Fructus arctii on cell proliferation and fibrosis, confirming its reliance on the Apoh/PPAR-γ pathway.

CONCLUSION

Fructus arctii alleviated DN progression by modulating cell proliferation and renal fibrosis via the Apoh/PPAR-γ pathway.

摘要

背景

糖尿病肾病（DN）的特征是肾纤维化和功能衰退。载脂蛋白H（Apoh）和传统药用植物牛蒡子已显示出治疗代谢和纤维化疾病的潜力。本研究着重揭示Apoh和牛蒡子在减轻糖尿病肾病中的作用。

方法

将db/db小鼠作为体内糖尿病肾病模型，用高糖（HG）处理小鼠肾小球系膜细胞（mMCs）和肾小管上皮细胞（mTECs）以在体外模拟糖尿病肾病。使用shRNA和pcDNA3.1载体进行Apoh基因沉默和过表达。将牛蒡子应用于细胞和动物模型以评估其治疗潜力。使用CCK-8和EdU试验测量细胞增殖，同时通过蛋白质免疫印迹、免疫组化和逆转录定量聚合酶链反应分析纤维化标志物。通过用拮抗剂GW9662处理来确认过氧化物酶体增殖物激活受体γ（PPAR-γ）途径的参与。用苏木精-伊红染色、过碘酸雪夫染色、马松三色染色和天狼星红染色等组织学染色评估肾脏结构变化。

结果

在经HG处理的细胞和db/db小鼠的肾脏中，Apoh表达明显降低。Apoh过表达通过下调细胞周期蛋白D1和增殖细胞核抗原抑制HG诱导的mMCs和mTECs增殖。此外，Apoh过表达通过降低纤连蛋白、I型胶原蛋白和α-平滑肌肌动蛋白水平减轻纤维化，这些作用是通过PPAR-γ途径介导的。用PPAR-γ拮抗剂GW9662处理可逆转这些保护作用。在db/db小鼠中，给予牛蒡子可通过降低血糖、蛋白尿和肾脏胶原沉积来改善肾功能。它还减轻了纤维化并增强了Apoh和PPAR-γ的表达。沉默Apoh消除了牛蒡子对细胞增殖和纤维化的保护作用，证实其依赖于Apoh/PPAR-γ途径。