Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China.
Department of Pharmacy, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
J Diabetes Investig. 2020 Mar;11(2):297-306. doi: 10.1111/jdi.13119. Epub 2019 Jul 23.
AIMS/INTRODUCTION: Amelioration of renal impairment is the key to diabetic nephropathy (DN) therapy. The progression of DN is closely related to podocyte dysfunction, but the detailed mechanism has not yet been clarified. The present study aimed to explore the renal impairment amelioration effect of berberine and related mechanisms targeting podocyte dysfunction under the diabetic state.
Streptozotocin (35 mg/kg) was used to develop a DN rat model together with a high-glucose/high-lipid diet. Renal functional parameters and glomerular ultrastructure changes were recorded. The alterations of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and phosphorylated Akt in the kidney cortex were determined by western blot. Meanwhile, podocyte dysfunction was induced and treated with berberine and LY294002. After that, podocyte adhesion functional parameters, protein biomarker and the alterations of the PI3K-Akt pathway were detected.
Berberine reduces the increased levels of biochemical indicators, and significantly improves the abnormal expression of PI3K, Akt and phosphorylated Akt in a rat kidney model. In vitro, a costimulating factor could obviously reduce the podocyte adhesion activity, including decreased expression of nephrin, podocin and adhesion molecule α3β1 levels, to induce podocyte dysfunction, and the trends were markedly reversed by berberine and LY294002 therapy. Furthermore, reduction of PI3K and phosphorylated Akt levels were observed in the berberine (30 and 60 μmol/L) and LY294002 (40 μmol/L) treatment group, but the Akt protein expression showed little change.
Berberine could be a promising antidiabetic nephropathy drug through ameliorating renal impairment and inhibiting podocyte dysfunction in diabetic rats, and the underlying molecular mechanisms might be involved in the regulation of the PI3K-Akt signaling pathway.
目的/引言：改善肾功能是糖尿病肾病（DN）治疗的关键。DN 的进展与足细胞功能障碍密切相关，但详细机制尚不清楚。本研究旨在探讨小檗碱在糖尿病状态下针对足细胞功能障碍改善肾功能损害的作用及相关机制。
采用链脲佐菌素（35mg/kg）联合高糖高脂饮食建立 DN 大鼠模型。记录肾功能参数和肾小球超微结构变化。采用 Western blot 检测肾皮质中磷脂酰肌醇 3-激酶（PI3K）、蛋白激酶 B（Akt）和磷酸化 Akt 的变化。同时，用小檗碱和 LY294002 诱导足细胞功能障碍并进行处理。然后，检测足细胞黏附功能参数、蛋白标志物和 PI3K-Akt 通路的变化。
小檗碱降低了生化指标的升高水平，并显著改善了大鼠肾脏模型中 PI3K、Akt 和磷酸化 Akt 的异常表达。在体外，一种共刺激因子可明显降低足细胞黏附活性，包括下调足细胞黏附分子α3β1、nephrin 和 podocin 的表达，从而诱导足细胞功能障碍，而小檗碱和 LY294002 治疗可明显逆转这些趋势。此外，在小檗碱（30 和 60μmol/L）和 LY294002（40μmol/L）治疗组中观察到 PI3K 和磷酸化 Akt 水平降低，但 Akt 蛋白表达变化不大。
小檗碱可通过改善糖尿病大鼠的肾功能损害和抑制足细胞功能障碍，成为一种有前途的抗糖尿病肾病药物，其潜在的分子机制可能涉及调节 PI3K-Akt 信号通路。
