Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4–Stat5–NF-κB pathway

医学 盐皮质激素受体 树突状细胞 染色质免疫沉淀 基因敲除 流式细胞术 内分泌学 过继性细胞移植 癌症研究 血管紧张素II 内科学 免疫学 T细胞 受体 细胞培养 生物 免疫系统 遗传学 基因 生物化学 基因表达 发起人
作者
Wei Wang,Hong Zhu,Yi-Tong Pan,Da Shang,Lin‐Juan Du,Lan Bai,Shiwei Zhu,Wen-Zhen Lin,Xingyu Zhang,Haixia Lü,Chao Bi,Yuan Liu,Yan Liu,Hui Xiao,Youcun Qian,Bin Zhou,Ruogu Li,Sheng‐Zhong Duan
出处
期刊:European Heart Journal [Oxford University Press]
标识
DOI:10.1093/eurheartj/ehae670
摘要

Abstract Background and Aims Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. Methods Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. Results Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. Conclusions Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4–Stat5–NF-κB signalling, and blockade of DC MR is beneficial for treating hypertension.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1234发布了新的文献求助10
刚刚
coconut完成签到,获得积分10
刚刚
winteryoung发布了新的文献求助10
1秒前
1秒前
1秒前
2秒前
2秒前
2秒前
2秒前
璐_发布了新的文献求助30
3秒前
哎嘿应助ll采纳,获得10
3秒前
3秒前
4秒前
txmjsn完成签到,获得积分10
5秒前
潇洒毛发布了新的文献求助10
6秒前
春风失意完成签到,获得积分10
7秒前
zxvcbnm完成签到,获得积分10
7秒前
所所应助Lin采纳,获得10
7秒前
向日葵应助梦里格斗家采纳,获得10
8秒前
sanso发布了新的文献求助10
8秒前
baibai完成签到,获得积分10
8秒前
9秒前
天天快乐应助虾米YYY采纳,获得10
9秒前
小虫子完成签到,获得积分20
10秒前
zzzzzz完成签到,获得积分10
10秒前
Rdx完成签到,获得积分10
10秒前
俏皮含烟完成签到,获得积分20
10秒前
慕青应助777采纳,获得10
10秒前
完美世界应助如意歌曲采纳,获得10
12秒前
13秒前
15秒前
15秒前
15秒前
乾坤发布了新的文献求助10
15秒前
16秒前
16秒前
19秒前
19秒前
19秒前
优秀不愁发布了新的文献求助10
19秒前
高分求助中
Evolution 10000
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Diagnostic immunohistochemistry : theranostic and genomic applications 6th Edition 500
Chen Hansheng: China’s Last Romantic Revolutionary 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3148410
求助须知:如何正确求助?哪些是违规求助? 2799502
关于积分的说明 7835226
捐赠科研通 2456813
什么是DOI,文献DOI怎么找? 1307424
科研通“疑难数据库(出版商)”最低求助积分说明 628189
版权声明 601655