Preliminary investigation of mechanism underlying Klotho insufficiency-induced spontaneous hypertension in mice

Zhaoying DONG; Xiaoli ZHOU

doi:10.16016/j.1000-5404.201909150

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Preliminary investigation of mechanism underlying Klotho insufficiency-induced spontaneous hypertension in mice

Basic Medicine | 更新时间：2026-01-09

- Preliminary investigation of mechanism underlying Klotho insufficiency-induced spontaneous hypertension in mice
- Journal of Third Military Medical University Vol. 42, Issue 4, Pages: 401-406(2020)
- 作者机构：
  
  400016 重庆，重庆医科大学附属第一医院心血管内科
- 作者简介：
- 基金信息：
  
  the Basic Science and Frontier Technology Research Project of Chongqing(CSTC2016jcyjA0201)
- DOI：10.16016/j.1000-5404.201909150
  CLC： R-332; R363.21; R544.1
- Received：19 September 2019，
  
  Revised：2019-11-25，
  
  Published：28 February 2020
- 稿件说明：
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Zhaoying DONG, Xiaoli ZHOU. Preliminary investigation of mechanism underlying Klotho insufficiency-induced spontaneous hypertension in mice[J]. Journal of Third Military Medical University, 2020, 42(4): 401-406.
DOI：

Zhaoying DONG, Xiaoli ZHOU. Preliminary investigation of mechanism underlying Klotho insufficiency-induced spontaneous hypertension in mice[J]. Journal of Third Military Medical University, 2020, 42(4): 401-406. DOI： 10.16016/j.1000-5404.201909150.

摘要

目的

探讨小鼠体内Klotho (KL)缺乏对血压的影响及其初步机制。

方法

使用KL基因半敲除129Sv小鼠作为实验组(KL

+/-

组)，同种系同龄129Sv小鼠作为对照组(WT组)，每组各20只。自10周龄起，应用无创VPR tail-cuff法监测小鼠血压，每周2次，至23周龄结束。取小鼠尿液，采用ELISA法检测小鼠尿微量白蛋白水平；心脏穿刺取血，ELISA法检

测小鼠醛固酮水平，尿素、肌酐测定试剂盒检测血尿素、肌酐水平；取肾脏制备石蜡切片

HE染色观察肾脏组织病理结构；免疫组织化学法检测肾脏KL蛋白表达；Masson染色观察肾脏纤维化水平，并进行半定量分析；Western blot测定肾脏组织中KL、SGK1、NCC、ATP synthase β蛋白的表达。

结果

与WT组比较，KL

+/-

组小鼠肾脏KL蛋白水平显著下降(

0.01)；自16周龄起出现持续、自发的血压升高；23周龄末KL

+/-

组小鼠尿白蛋白与血肌酐比值、血肌酐和血尿素水平增高，肾脏病理重塑和纤维化明显(

0.01)；小鼠醛固酮水平升高且SGK1、NCC、ATP synthase β蛋白表达显著升高(

0.05)。

结论

体内KL的减少可能导致小鼠自发性血压升高，其机制可能与KL缺乏导致的肾脏损害和醛固酮水平升高所致的水钠潴留相关。

Abstract

Objective

To investigate the mechanism of Klotho (KL) insufficiency-induced spontaneous hypertension in mice.

Methods

We monitored blood pressure using high-throughput non-invasive blood pressure cuff in 10-week-old 129Sv mice with partial KL gene knockout (KL

+/-

) and wide-type 129Sv mice of the same age (

=20) twice a week till the mice were 23 weeks old. Urine samples of the mice were collected for measuring the level of microalbumin using enzyme-linked immunosorbent assay (ELISA). The levels of aldosterone

urea and creatinine in cardiac blood were determined using ELISA or commercial kits. HE staining was used to observe the pathological changes in the kidney

and the expression level of KL in the renal tissues was analyzed immunohistochemically; renal fibrosis was assessed using Masson staining. The protein expressions of KL

SGK1

NCC and ATP synthase β were detected using Western blotting.

Results

Compared with those in the wild-type mice

the expression level of KL protein in the renal tissue was significantly decreased in KL

+/-

mice (

0.01). The KL

+/-

mice showed significantly increased blood pressure since 16 weeks of age with sustained hypertension. At the end of 23 weeks

the KL

+/-

presented with significantly increased urinary al

bumin/serum creatinine ratio and serum levels of creatinine and urea

showing also obvious pathological remodeling and fibrosis in the kidney (

0.01) and increased renal expression of aldosterone

SGK1

NCC and ATP synthase β (

0.01).

Conclusion

KL insufficiency may result in spontaneous blood pressure elevation possibly due to structural and functional impairment of the kidneys and water and sodium retention induced by a high aldosterone level.

关键词

Keywords

references

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