Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Phytomedicine. 2022 Sep;104:154276. doi: 10.1016/j.phymed.2022.154276. Epub 2022 Jun 13.
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. DN is the main cause of end-stage renal disease (ESRD). SIRT6 becomes the important target of DN. Diosgenin (a monomer from Chinese herbs) is probable to bind to SIRT6.
Based on studies presented in the literature on kidney injuries plus screening for the binding effects of the drug to Sirt6, we aimed to carry out the study to assess the effects of diosgenin involved in improving podocyte damage in the early phase of DN..
DN model was established in spontaneous diabetic db/db mice. Animal experiment was in two parts. The first part includes four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part includes four groups consisting of control group, model group, DH+OSS_128167 (OSS, inhibitor of SIRT6) group, MDL800 (agonist of SIRT6) group. MPC5 cell line was selected in cell experiment, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL800 group. Some procedures such as transcriptomics, RT-qPCR and so on were used in the study to explore and verify the mechanism.
The abnormal changes of mesangial matrix expansion, glomerular basement membrane (GBM) thickness, foot process (FP) width, urine albumin/creatinine (UACR), DESMIN, ADRP, NEPHRIN, PODOCIN, SIRT6 in Mod group were alleviated in DH group rather than DL group in the first part of animal experiment. The effect in DH group could be reversed in DH+OSS group and the same effect was observed in MDL800 group in the second part of animal experiment. The same results were also found in cell experiment. Protein level and mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and Angiopoietin-like-4 (ANGPTL4) were increased in PA group, which could be alleviated in DH group, MDL800 group rather than DH+OSS group.
Diosgenin could protect against podocyte injury in early phase of diabetic nephropathy by regulating SIRT6.
糖尿病肾病（DN）是糖尿病的一种严重并发症。DN 是终末期肾病（ESRD）的主要原因。SIRT6 成为 DN 的重要靶点。薯蓣皂素（一种来自中草药的单体）可能与 SIRT6 结合。
基于文献中关于肾脏损伤的研究以及对药物与 Sirt6 结合效应的筛选，本研究旨在评估薯蓣皂素在改善 DN 早期阶段足细胞损伤中的作用。
在自发性糖尿病 db/db 小鼠中建立 DN 模型。动物实验分为两部分。第一部分包括 4 组：对照组（Con）、模型组（Mod）、低剂量薯蓣皂素组（DL）和高剂量薯蓣皂素组（DH）。第二部分包括 4 组：对照组、模型组、DH+OSS_128167（OSS，SIRT6 抑制剂）组、MDL800（SIRT6 激动剂）组。细胞实验主要包括 6 组：对照组（Con）、棕榈酸（PA）组、PA+DL 组、PA+DH 组、PA+DH+OSS 组、PA+MDL800 组。采用转录组学、RT-qPCR 等方法进行研究，以探索和验证机制。
在动物实验的第一部分中，DH 组可减轻系膜基质扩张、肾小球基底膜（GBM）厚度、足突（FP）宽度、尿白蛋白/肌酐（UACR）、DESMIN、ADRP、NEPHRIN、PODOCIN、SIRT6 等指标的异常变化，而 DL 组则无此作用。DH+OSS 组可逆转 DH 组的作用，MDL800 组也有相同的作用。细胞实验也得到了相同的结果。PA 组丙酮酸脱氢酶激酶 4（PDK4）和血管生成素样蛋白 4（ANGPTL4）的蛋白水平和 mRNA 表达增加，DH 组、MDL800 组而非 DH+OSS 组可减轻。
薯蓣皂素可通过调节 SIRT6 来保护糖尿病肾病早期的足细胞损伤。
