目的·探讨天然化合物金丝桃素（hypericin，HYP）对糖尿病肾病（diabetic nephropathy，DN）足细胞损伤的保护作用及其可能的分子机制。方法·选取18只db/db小鼠构建DN模型，随机分为模型组、db/db+HYP低剂量组（db/db+HYP-L，1.5 mg/kg）、db/db+HYP高剂量组（db/db+HYP-H，3.0 mg/kg），并设6只db/m小鼠为正常对照组。检测各组小鼠空腹血糖（fasting blood glucose，FBG）、胰岛素（insulin，INS）、总胆固醇（total cholesterol，TC）、甘油三酯（triglyceride，TAG）、低密度脂蛋白（low-density lipoprotein，LDL）、高密度脂蛋白（high-density lipoprotein，HDL）、血肌酐（serum creatinine，Scr）、血尿素氮（blood urea nitrogen，BUN）、尿白蛋白/肌酐比值（urinary albumin-to-creatinine ratio，UACR）及炎症因子［肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白细胞介素-1β（interleukin-1β，IL-1β）、白细胞介素-6（interleukin-6，IL-6）、单核细胞趋化蛋白-1（monocyte chemoattractant protein-1，MCP-1）］水平。经苏木精-伊红（hematoxylin-eosin，HE）、过碘酸-希夫（periodic acid Schiff，PAS）染色以及透射电镜观察各组小鼠肾脏病理变化及足细胞超微结构。免疫组化及蛋白质印迹法（Western blotting）检测各组小鼠肾组织中足细胞标志物Wilms瘤1（Wilms tumor 1，WT-1）的表达。蛋白质印迹法检测肾组织核因子κB（nuclear factor-κB，NF-κB）的表达水平。体外培养人足细胞系，建立高糖诱导足细胞损伤模型，实验分为5组：正常糖组（5.5 mmol/L glucose，NG）、甘露醇组（5.5 mmol/L glucose+24.5 mmol/L mannitol，MA）、高糖组（30 mmol/L glucose，HG）、高糖+HYP 0.05 μg/mL组（HG+0.05 μg/mL HYP）、高糖+HYP 0.20 μg/mL组（HG+0.20 μg/mL HYP），48 h后收集细胞。通过蛋白质印迹法检测WT-1、p-NF-κB p65、NF-κB p65蛋白水平，实时荧光定量PCR（quantitative real-time，qPCR）检测各组人足细胞炎症因子（TNF-α、IL-1β、IL-6、MCP-1）的mRNA水平。结果·与模型组相比，HYP显著降低db/db小鼠FBG、INS、TC、TAG、LDL、Scr、BUN及UACR水平，显著升高HDL水平（均P<0.05），并减轻db/db小鼠足细胞损伤，表现为足突融合现象显著减轻，足突排列重现梳子齿状。体内和体外研究均发现，HYP上调WT-1表达，同时抑制NF-κB p65磷酸化及其介导的炎症因子（TNF-α、IL-1β、IL-6、MCP-1）释放（均P<0.05）。结论·HYP可以减轻db/db小鼠足细胞损伤，其作用可能与上调WT-1表达、抑制NF-κB通路、下调炎症因子表达有关。

Objective ·To investigate the protective effect of the natural compound hypericin (HYP) on podocyte injury in diabetic nephropathy (DN) and its underlying molecular mechanism. Methods ·A total of eighteen db/db mice were selected to establish the DN model and were randomly divided into three groups: the model group, the db/db + HYP low-dose group (db/db+HYP-L, 1.5 mg/kg), and the db/db+HYP high-dose group (db/db+HYP-H, 3 mg/kg). Additionally, six db/m mice were designated as the normal control group. The following parameters were measured in mice from each group: fasting blood glucose (FBG), insulin (INS), total cholesterol (TC), triglyceride (TAG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), serum creatinine (Scr), blood urea nitrogen (BUN), urinary albumin-to-creatinine ratio (UACR), as well as levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Renal pathological changes and podocyte ultrastructure in mice from each group were examined by hematoxylin-eosin (HE) staining, periodic acid-Schiff (PAS) staining, and transmission electron microscopy. The expression of the podocyte marker Wilms tumor 1 (WT-1) in renal tissues from each group was assessed using immunohistochemistry and Western blotting. The protein expression level of nuclear factor-κB (NF-κB) was also measured by Western blotting. Human podocyte lines were cultured in vitro to establish a high-glucose-induced podocyte injury model. The experiment was divided into five groups: normal glucose (5.5 mmol/L glucose, NG), mannitol (5.5 mmol/L glucose+24.5 mmol/L mannitol, MA), high glucose (30.0 mmol/L glucose, HG), high glucose+0.05 μg/mL HYP, and high glucose+0.20 μg/mL HYP. Cells were harvested after 48 h of incubation. The protein levels of WT-1, phospho-NF-κB p65 (p-NF-κB p65), and NF-κB p65 were determined by Western blotting. The mRNA expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1) in human podocytes across all groups were measured by quantitative real-time PCR (qPCR). Results ·Compared with the model group, HYP administration significantly reduced the levels of FBG, INS, TC, TAG, LDL, Scr, BUN, and UACR in db/db mice, while significantly increasing the level of HDL (all P<0.05). Concomitantly, HYP alleviated podocyte injury in db/db mice, as evidenced by a marked reduction in foot process effacement and restoration of a comb-like alignment of the foot processes. Both in vivo and in vitro studies demonstrated that HYP upregulated the expression of WT-1 while concurrently suppressing the phosphorylation of NF-κB p65 and the subsequent release of NF-κB-mediated inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1) (all P<0.05). Conclusion ·HYP alleviates podocyte injury in db/db mice, an effect that may be attributed to the upregulation of WT-1 expression and inhibition of the NF-κB signaling pathway, leading to reduced expression of downstream inflammatory cytokines.