Effect of Astragaloside Ⅳ on Regulation of PI3K/Akt/FoxO1 Signal in Kidney of Type 2 Diabetic Nephropathy Rats

Ke-ke MA; Ying-hui JU; Qing-qing CHEN; Wei-zu LI; Wei-ping LI

doi:10.13422/j.cnki.syfjx.20190227

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Effect of Astragaloside Ⅳ on Regulation of PI3K/Akt/FoxO1 Signal in Kidney of Type 2 Diabetic Nephropathy Rats

Pharmacology | 更新时间：2021-02-09

- Effect of Astragaloside Ⅳ on Regulation of PI3K/Akt/FoxO1 Signal in Kidney of Type 2 Diabetic Nephropathy Rats
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 25, Issue 2, Pages: 74-81(2019)
- 作者机构：
  
  1.安徽医科大学　基础医学院，合肥　 230032;
  2.安庆医药高等专科学校，安徽　安庆　 246052
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20190227
  CLC： R2-0; R22; R285.5
- Received：18 June 2018，
  
  Published Online：02 November 2018，
  
  Published：20 January 2019
- 稿件说明：
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Ke-ke MA, Ying-hui JU, Qing-qing CHEN, et al. Effect of Astragaloside Ⅳ on Regulation of PI3K/Akt/FoxO1 Signal in Kidney of Type 2 Diabetic Nephropathy Rats[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(2): 74-81.
DOI：

Ke-ke MA, Ying-hui JU, Qing-qing CHEN, et al. Effect of Astragaloside Ⅳ on Regulation of PI3K/Akt/FoxO1 Signal in Kidney of Type 2 Diabetic Nephropathy Rats[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(2): 74-81. DOI： 10.13422/j.cnki.syfjx.20190227.

摘要

目的：

研究黄芪甲苷对2型糖尿病肾病大鼠肾脏的保护作用及其对磷酯酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/叉头框转录因子O亚族1(FoxO1)信号的调控作用，探讨黄芪甲苷保护2型糖尿病肾病的机制。

方法：

6周高糖高脂饮食后，给予链脲佐菌素(STZ)一次性腹腔注射(35 mg·kg

－1

)建立2型糖尿病大鼠模型，随机分为正常组，模型组，黄芪甲苷(20，40，80 mg·kg

－1

)组及盐酸二甲双胍(阳性药)组。连续给药8周后检测各组大鼠体质量，肾脏指数，血糖，24 h尿蛋白，尿微量白蛋白，尿肌酐，血肌酐及血尿素氮含量的变化；苏木素-伊红(HE)染色观察肾脏组织病理形态学变化；马松(Masson)三色染色观察胶原表达水平；过碘酸六胺银(PASM)染色观察基底膜的变化；免疫组化检测磷酸化FoxO1(p-FoxO1)蛋白表达；蛋白质免疫印迹法(Western blot)分析PI3K/Akt/FoxO1信号蛋白及自噬标记蛋白PI3K，微管相关蛋白1轻链3(LC3)Ⅰ/Ⅱ，B细胞淋巴瘤-2(Bcl-2)/腺病毒E1B 19 kDa相互作用蛋白3(BNIP3)，Beclin1，p-Akt，Akt表达水平。

结果：

与正常组比较，模型组肾小球基底膜增厚，细胞外基质增多，系膜扩张，胶原蛋白显著增加，PI3K/Akt/FoxO1信号增强(

0.01)，自噬活性减弱(

0.01)；与模型组比较，黄芪甲苷中、高剂量肾脏组织病变明显改善，明显抑制肾组织PI3K，Akt及FoxO1磷酸化水平(

0.05，

0.01)，同时增强自噬反应，上调BNIP3，LC3 Ⅱ/LC3 Ⅰ和Beclin1的表达(

0.05，

0.01)。

结论：

黄芪甲苷可能通过抑制PI3K/Akt/FoxO1信号增加肾组织细胞自噬活性，减缓了2型糖尿病肾病的发展进程。

Abstract

Objective:

To study the protective effect of astragaloside (AS) Ⅳ on kidney in type 2 diabetic nephropathy rats and its regulation effect on phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O1(FoxO1) signaling

and investigate the mechanism of glycosides against type 2 diabetic nephropathy.

Method:

After 6 weeks of high-glucose and high-fat diet

rat models of type 2 diabetes were established by intraperitoneal injection of streptozotocin (STZ) (35 mg·kg

-1

) and randomly divided into model group

AS-Ⅳ (20

80 mg·kg

-1

) groups and metformin hydrochloride (positive) group. After 8 weeks of continuous administration

changes in body weight

kidney index

blood glucose

24-hour urinary protein

urinary microalbumin

urinary creatinine

serum creatinine

and blood urea nitrogen were measured in each group; hematoxylin-eosin (HE) staining was used to observe the pathological changes of renal tissues; Masson trichrome staining was used to observe the collagen expression level. Periodontium hexaammine silver (PASM) staining was used to observe the changes of basement membrane. Immunohistochemistry assay was used to detect phospho-FoxO1(p-FoxO1) protein expression

and Western blot was used to analyze the expression levels of autophagy marker protein PI3K

microtubule-associated protein 1 light chain 3 (LC3)/Ⅱ

B-cell lymphoma-2 (Bcl-2)/adenovirus E1B19 kDa interacting protein 3 (BNIP3)

Beclin1

p-Akt

and Akt.

Result:

As compared with the normal group

the glomerular basement membrane of the model group was thicker; the extracellular matrix was increased; the mesangial was expanded; the collagen was significantly increased; the PI3K/Akt/FoxO1 signal was increased(

0.01); and the autophagic activity was weakened (

0.01). As compared with the model group

the phosphorylation of PI3K

Akt

and FoxO1 in renal tissue was significantly inhibited in AS-Ⅳ high and medium dose groups (

0.05

0.01); autophagy was increased; and the expression of BNIP3

LC3 Ⅱ/LC3 I

and Beclin1 was up-regulated (

0.05

0.01).

Conclusion:

AS-Ⅳ may increase the autophagic activity of renal cells by inhibiting PI3K/Akt/FoxO1 signal

slowing down the development of type 2 diabetic nephropathy.

关键词

Keywords

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