目的 探讨桑白皮总黄酮改善高脂血症并高尿酸血症相关肾病的作用机制。方法 选取桑白皮总黄酮提取物（TFMC）中有效成分桑辛素及尿酸相关基因，将桑辛素与同源建模所得的URAT1蛋白结构进行分子对接。将40只SD大鼠随机分为对照组、模型组、TFMC组（1.0 g/kg）和苯溴马隆组（6.25 mg/kg）。采用高脂饲料喂养联合ig腺嘌呤加乙胺丁醇的方法制备高脂血症并高尿酸血症模型。各给药组大鼠ig给药16周后，检测大鼠血清中血糖（Glu）、总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、尿酸（UA）、肌酐（CRE）、尿素氮（BUN）水平；苏木素-伊红染色观察肾脏病理改变；实时荧光定量PCR（qRT-PCR）检测肾脏组织白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、尿酸盐阴离子交换转运体1（URAT1）、有机阴离子转运体1（OAT1）mRNA的表达。结果 TFMC主要成分桑辛素与URAT1对接打分较高，提示桑辛素可能是TFMC中改善高脂血症并高尿酸血症相关肾病的主要活性成分。药物干预16周后，与对照组比较，模型组大鼠血清中Glu、TC、TG、LDL-C、UA、CRE、BUN水平均显著升高，HDL-C水平显著降低（P<0.05、0.01）。与模型组比较，TFMC组大鼠和苯溴马隆组Glu、TC、TG、LDL-C、UA、CRE、BUN水平均显著下降，HDL-C水平显著升高（P<0.05、0.01）。HE染色结果显示，与对照组比较，模型组大鼠肾小管上皮细胞发生肿胀及坏死，肾小管中可见明显的蛋白管型。TFMC组部分肾小管上皮细胞有轻微肿胀，周围未见炎性细胞浸润。苯溴马隆组大鼠肾皮质、髓质结构清晰，肾小球未见增生或萎缩，管腔中未见管型，肾间质未见炎性细胞浸润。qRT-PCR结果显示，与对照组比较，模型组大鼠肾组织IL-6、TNF-α、URAT1 mRNA表达水平均显著升高，OAT1 mRNA表达水平显著降低（P<0.05）。与模型组比较，TFMC组大鼠肾组织IL-6、TNF-α、URAT1 mRNA表达水平显著降低，OAT1 mRNA表达水平显著升高（P<0.05、0.01）。结论 TFMC改善高脂血症并高尿酸血症相关肾病可能与其调节IL-6、TNF-α、URAT1、OAT1 mRNA等有关，URAT1可能是其潜在靶点，分子虚拟对接和动物实验结果具有一定的相似性，为进一步探讨TFMC改善高脂血症并高尿酸血症相关肾病提供理论基础，为后续分子机制深入研究提供参考。

Objective To investigate the mechanism of total flavonoids of Mori Cortex (TFMC) in improving hyperlipidemia and hyperuricemia related nephropathy. Methods The molecular structure of URAT1 protein and structure of Mori Cortex total flavonoids extract were docked by selecting the effective components of total flavonoids extract of Mori Cortex and related genes of uric acid. Forty SD rats were randomly divided into four groups:normal group, model group, TFMC group (1.0 g/kg) and benzbromarone group (6.25 mg/kg). The hyperlipidemia and hyperuricemia model was established by feeding with high fat diet plus adenine and ethylamine butanol. After 16 weeks, the levels of blood glucose and blood lipids in serum, uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) of rats in each group were compared. The renal pathological changes were observed by hematoxylin eosin staining. The expressions of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), uric acid anion exchange transporter 1 (URAT1) and organic anion transporter 1 (OAT1) were detected by qRT-PCR. Results The main component of moracin of total flavonoids of Mori Cortex was the high target of the genes related to uric acid, suggesting that the moracin might be the main active component in the improvement of hyperlipidemia and hyperuricemia related nephropathy. After 16 weeks of drug intervention, the serum levels of Glu, TC, TG, LDL-C, UA, CRE and BUN in the model group were significantly higher than those in the normal group, and the level of HDL-C in the model group was significantly higher than that in the normal group (P < 0.05, 0.01). Compared with the model group, the above biochemical indexes in the TFMC group and the benzbromarone group were significantly decreased and HDL-C was significantly increased (P < 0.05, 0.01). The results of HE staining showed that the epithelial cells of renal tubules in the model group were swollen and necrotized, and the protein tubules could be seen in the renal tubules. In the TFMC group, some renal tubular epithelial cells were slightly swollen, and no inflammatory cells infiltrated around them. The structures of renal cortex and medullary were clear, and no hyperplasia or atrophy in glomerular were found, no tubular type and inflammatory cell infiltration in renal interstitial tissue of rats in benzbrommarone group were observed. The results of qRT-PCR showed that, compared with the normal group, the content of IL-6, TNF-α, and URAT1 mRNA was significantly increased, the content of OAT1 mRNA was significantly decreased in the model group; The content of above indicators was decreased and OAT1 was increased after drug intervention, (P < 0.05, 0.01). Conclusion The improvement of hyperlipidemia and hyperuricemia associated nephropathy may be related to the regulation of IL-6, TNF-α, URAT1, and OAT1 mRNA. Mori Cortex has obvious influence on the key factor of hyperlipidemia and hyperuricemia with URAT1 as its potential target, and the results of molecular virtual docking and animal experiments are similar. It provides a theoretical basis for further study on the improvement of hyperlipidemia and hyperuricemia related nephropathy and provides a reference for the further molecular mechanism.

国家自然科学基金资助项目（81373775）