Yang Xi-Ding, Ma Si-Jia, Xiang Da-Xiong, Yang Yong-Yu
Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China.
World J Diabetes. 2025 May 15;16(5):102196. doi: 10.4239/wjd.v16.i5.102196.
Injury to the glomerular filtration barrier causes diabetic kidney disease (DKD), and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells. Shenfushu granules (SFSGs) can treat chronic renal failure; however, their role and mechanism in DKD remain unclear.
To investigate the role of SFSGs in delaying DKD progression and their underlying mechanism in a streptozotocin-induced DKD mouse model.
The microalbumin content in the urine and the blood glucose, creatinine, and blood urea nitrogen levels in the serum were measured. The expression and distribution of α-smooth muscle actin (α-SMA), heparan sulfate (HS) and cluster of differentiation (CD) 31 were observed through immunofluorescence or immunohistochemistry. Western blotting was conducted to measure the expression of CD31, α-SMA, , protein kinase B (AKT), phospho-, phospho-AKT, and heparanase-1. Network pharmacology was conducted to screen and identify the core components and targets of SFSGs. Molecular docking and dynamic simulations were performed to evaluate the binding ability of the core components of SFSGs to their core targets.
Compared with those in the model group, the 24-hour microalbuminuria (188.2 ± 20.1 and 140.4 ± 24.7 323.2 ± 44.4), serum creatinine (79.4 ± 2.6 and 68.7 ± 6.0 110.2 ± 4.8), blood urea nitrogen (14.4 ± 1.1 and 13.1 ± 0.5 19.5 ± 1.1), and renal index (20.3 ± 1.0 and 19.6 ± 0.8 25.3 ± 1.7) were significantly lower in the SFSGs (2.08 and 4.16 g/kg/day extract)-treated DKD mice. SFSGs inhibited the downregulation of CD31 and the upregulation of α-SMA in the glomerular endothelial cells of DKD mice. Additionally, SFSGs suppressed the decrease in glycocalyx thickness and the expression of its component HS. Network pharmacology revealed that was the core target of SFSGs. SFSGs markedly downregulate the expression of phospho-, phospho-AKT, and heparanase-1. However, the agonist abolished the regulatory effect of SFSGs on the expression of CD31, α-SMA, and heparanase-1.
Collectively, these results suggest that SFSGs can significantly delay DKD progression and inhibit injury to the glycocalyx and the endothelial-mesenchymal transition of glomerular endothelial cells. This mechanism is related to /AKT/heparanase-1 signaling pathway regulation.
肾小球滤过屏障损伤会导致糖尿病肾病（DKD），而肾小球内皮 - 间充质转化会损害肾小球内皮细胞的滤过屏障。参附舒颗粒（SFSGs）可治疗慢性肾衰竭；然而，其在DKD中的作用及机制仍不清楚。
在链脲佐菌素诱导的DKD小鼠模型中，研究SFSGs在延缓DKD进展中的作用及其潜在机制。
检测尿液中的微量白蛋白含量以及血清中的血糖、肌酐和血尿素氮水平。通过免疫荧光或免疫组织化学观察α - 平滑肌肌动蛋白（α - SMA）、硫酸乙酰肝素（HS）和分化簇（CD）31的表达及分布。进行蛋白质印迹法检测CD31、α - SMA、蛋白激酶B（AKT）、磷酸化 - 、磷酸化AKT和乙酰肝素酶 - 1的表达。采用网络药理学筛选并鉴定SFSGs的核心成分和靶点。进行分子对接和动态模拟以评估SFSGs核心成分与其核心靶点的结合能力。
与模型组相比，SFSGs（提取物2.08和4.16 g/kg/天）治疗的DKD小鼠24小时微量白蛋白尿（分别为188.2±20.1和140.4±24.7对比323.2±44.4）、血清肌酐（分别为79.4±2.6和68.7±6.0对比110.2±4.8）、血尿素氮（分别为14.4±1.1和13.1±0.5对比19.5±1.1）和肾指数（分别为20.3±1.0和19.6±0.8对比25.3±1.7）显著降低。SFSGs抑制DKD小鼠肾小球内皮细胞中CD31的下调和α - SMA的上调。此外，SFSGs抑制糖萼厚度的降低及其成分HS的表达。网络药理学显示 是SFSGs的核心靶点。SFSGs显著下调磷酸化 - 、磷酸化AKT和乙酰肝素酶 - 1的表达。然而， 激动剂消除了SFSGs对CD31、α - SMA和乙酰肝素酶 - 1表达的调节作用。
总体而言，这些结果表明SFSGs可显著延缓DKD进展，抑制糖萼损伤和肾小球内皮细胞的内皮 - 间充质转化。该机制与/AKT/乙酰肝素酶 - 1信号通路调节有关。
