Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone mice by downregulating renal -actinin-4 expression and stabilizing integrin-cytoskeleton linkage

doi:10.1186/s13075-019-1820-3

	Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone mice by downregulating renal -actinin-4 expression and stabilizing integrin-cytoskeleton linkage
	He, Shijun 1,2; Liu, Xing 3,4; Lin, Zemin 1; Liu, Yuting 1,2; Gu, Lei 3,4; Zhou, Hu 2,3,4; Tang, Wei 1,2; Zuo, Jianping 1,2
刊名	ARTHRITIS RESEARCH & THERAPY
	2019-01-29
卷号	21 页码:16
关键词	SAHH inhibitor Lupus nephritis -Actinin-4 Integrin-linked kinase Integrin Focal adhesion
ISSN号	1478-6354
DOI	10.1186/s13075-019-1820-3
通讯作者	Zhou, Hu(zhouhu@simm.ac.cn) ; Tang, Wei(tangwei@simm.ac.cn) ; Zuo, Jianping(jpzuo@simm.ac.cn)
英文摘要	BackgroundGlomerulonephritis is one of the major complications and causes of death in systemic lupus erythematosus (SLE) and is characterized by glomerulosclerosis, interstitial fibrosis, and tubular atrophy, along with severe persistent proteinuria. DZ2002 is a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with potent therapeutic activity against lupus nephritis in mice. However, the molecular events underlying the renal protective effects of DZ2002 remained unclear. This study is designed to uncover the molecular mechanisms of DZ2002 on glomerulonephritis of lupus-prone mice.MethodsWe conducted a twice-daily treatment of DZ2002 on the lupus-prone NZB/WF1 mice, and the progression of lupus nephritis and alteration of renal function were monitored. The LC-MS-based label-free quantitative (LFQ) proteomic approach was applied to analyze the kidney tissue samples from the normal C57BL/6 mice and the NZB/WF1 mice treated with DZ2002 or vehicle. KEGG pathway enrichment and direct protein-protein interaction (PPI) network analyses were used to map the pathways in which the significantly changed proteins (SCPs) are involved. The selected proteins from proteomic analysis were validated by Western blot analysis and immunohistochemistry in the kidney tissues.ResultsThe twice-daily regimen of DZ2002 administration significantly ameliorated the lupus nephritis and improved the renal function in NZB/WF1 mice. A total of 3275 proteins were quantified, of which 253 proteins were significantly changed across normal C57BL/6 mice and the NZB/WF1 mice treated with DZ2002 or vehicle. Pathway analysis revealed that 13 SCPs were involved in tight junction and focal adhesion process. Further protein expression validation demonstrated that DZ2002-treated NZB/WF1 mice exhibited downregulation of -actinin-4 and integrin-linked kinase (ILK), as well as the restoration of 1-integrin activation in the kidney tissues compared with the vehicle-treated ones.ConclusionsOur study demonstrated the first evidence for the molecular mechanism of SAHH inhibitor on glomerulonephritis in SLE via the modulation of -actinin-4 expression and focal adhesion-associated signaling proteins in the kidney.
资助项目	Personalized Medicines--Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020215] ; Personalized Medicines--Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020107] ; National Basic Research Program of China (973 Program)[2014CB541906] ; National Nature Science foundation of China[81402939]
WOS关键词	FOOT PROCESS EFFACEMENT ; LINKED KINASE ; PROTEOMIC ANALYSIS ; POTENTIAL BIOMARKERS ; KIDNEY-DISEASE ; ALPHA-ACTININ ; ALPHA-ACTININ-4 ; BINDING ; ADHESION ; ILK
WOS研究方向	Rheumatology
语种	英语
出版者	BMC
WOS记录号	WOS:000457091800001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290627]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Hu; Tang, Wei; Zuo, Jianping
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	He, Shijun,Liu, Xing,Lin, Zemin,et al. Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone mice by downregulating renal -actinin-4 expression and stabilizing integrin-cytoskeleton linkage[J]. ARTHRITIS RESEARCH & THERAPY,2019,21:16.
APA	He, Shijun.,Liu, Xing.,Lin, Zemin.,Liu, Yuting.,Gu, Lei.,...&Zuo, Jianping.(2019).Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone mice by downregulating renal -actinin-4 expression and stabilizing integrin-cytoskeleton linkage.ARTHRITIS RESEARCH & THERAPY,21,16.
MLA	He, Shijun,et al."Reversible SAHH inhibitor protects against glomerulonephritis in lupus-prone mice by downregulating renal -actinin-4 expression and stabilizing integrin-cytoskeleton linkage".ARTHRITIS RESEARCH & THERAPY 21(2019):16.