Background

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.

Purpose

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..

Methods

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.

Results

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.

Conclusions

Diosgenin could protect against podocyte injury in early phase of diabetic nephropathy by regulating SIRT6.

中文翻译：

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薯蓣皂苷元通过调节 SIRT6 保护糖尿病肾病早期足细胞损伤

背景

糖尿病肾病（DN）是糖尿病的严重并发症。DN是终末期肾病（ESRD）的主要原因。SIRT6成为DN的重要目标。薯蓣皂苷元（一种来自中草药的单体）很可能与 SIRT6 结合。

目的

基于文献中关于肾损伤的研究以及药物与 Sirt6 结合作用的筛选，我们旨在开展这项研究，以评估薯蓣皂苷元在 DN 早期参与改善足细胞损伤的作用。

方法

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。第一部分包括对照组（Con）组、模型（Mod）组、低剂量薯蓣皂苷元（DL）组和高剂量薯蓣皂苷元（DH）组四组。第二部分包括对照组、模型组、DH+OSS_128167（OSS，SIRT6抑制剂）组、MDL800（SIRT6激动剂）组四组。细胞实验选用MPC5细胞系，主要由Con组、棕榈酸（PA）组、PA+DL组、PA+DH组、PA+DH+OSS组、PA+MDL800组6组组成。研究中使用了转录组学、RT-qPCR等程序来探索和验证机制。

结果

Mod组系膜基质扩张、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异常变化较DH组减轻。 DL组动物实验第一部分。DH+OSS组可以逆转DH组的作用，MDL800组在动物实验的第二部分观察到相同的作用。在细胞实验中也发现了相同的结果。PA组丙酮酸脱氢酶激酶4（PDK4）和血管生成素样4（ANGPTL4）蛋白水平和mRNA表达升高，DH组、MDL800组较DH+OSS组减轻。

结论

薯蓣皂苷元可通过调节 SIRT6 保护糖尿病肾病早期足细胞损伤。