Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys

doi:10.1111/bph.14687

科研成果详情

题名	Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys
作者	Wang, Yi1; Fang, Qilu 1; Jin, Yiyi 1; Liu, Zhoudi 1; Zou, Chunpeng2; Yu, Weihui3; Li, Weixin 1; Shan, Xiaoou 2; Chen, Ruijie2; Khan, Zia 1; Liang, Guang1
发表日期	2019-07
发表期刊	BRITISH JOURNAL OF PHARMACOLOGY 影响因子和分区
语种	英语
原始文献类型	Article
其他关键词	SUCCINATE RECEPTOR GPR91 ; PHARMACOLOGY 2017/18 ; CONCISE GUIDE ; INFLAMMATORY RESPONSE ; ALDOSTERONE SYSTEM ; RENAL INFLAMMATION ; OXIDATIVE STRESS ; MESANGIAL CELLS ; INHIBITION ; TLR4
摘要	Background and Purpose Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. Experimental Approach MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2(-/-) mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. Key Results Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-beta and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. Conclusions and Implications Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy.
资助项目	Natural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province [LY17H050007, LY18H290009, LY18H310012, LR16H310001, LR18H160003]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81603180, 81600659, 81770850, 81670768]; National Key Research Project [2017YFA0506000]
出版者	WILEY
出版地	HOBOKEN
ISSN	0007-1188
EISSN	1476-5381
卷号	176 期号:14 页码:2642-2657
DOI	10.1111/bph.14687
页数	16
WOS类目	Pharmacology & Pharmacy
WOS研究方向	Pharmacology & Pharmacy
WOS记录号	WOS:000472784200021
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	30959575
PMC记录号	PMC6592858
SCOPUSEID	2-s2.0-85066157240
自科自定义期刊分类	T3(B)类
通讯作者地址	[Wang, Yi]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China
Scopus学科分类	Pharmacology
引用统计	被引频次：23[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/12628
专题	药学院（分析测试中心）附属第二医院第二临床医学院、附属第二医院、育英儿童医院其他_附属乐清医院（乐清市人民医院）
通讯作者	Wang, Yi
作者单位	1.Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China; 2.The Second Affiliated Hospital,Wenzhou Medical University,Wenzhou,China; 3.Department of Endocrinology,The First Affiliated Yueqing Hospital,Wenzhou Medical University,Wenzhou,China
第一作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
通讯作者单位	药学院（分析测试中心）; 生物有机与药物化学研究中心
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Wang, Yi,Fang, Qilu,Jin, Yiyi,et al. Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys[J]. BRITISH JOURNAL OF PHARMACOLOGY,2019,176(14):2642-2657.
APA	Wang, Yi., Fang, Qilu., Jin, Yiyi., Liu, Zhoudi., Zou, Chunpeng., ... & Liang, Guang. (2019). Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys. BRITISH JOURNAL OF PHARMACOLOGY, 176(14), 2642-2657.
MLA	Wang, Yi,et al."Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys".BRITISH JOURNAL OF PHARMACOLOGY 176.14(2019):2642-2657.