Syndecan-1 Shedding Inhibition to Protect Against Ischemic Acute Kidney Injury Through HGF Target Signaling Pathway

被引:25
|
作者
Lu, Zhihui [1 ,2 ,3 ,4 ,5 ]
Song, Nana [1 ,2 ,3 ,4 ,5 ]
Shen, Bo [1 ,2 ,3 ,4 ,5 ]
Xu, XiaLian [1 ,2 ,3 ,4 ,5 ]
Fang, Yi [1 ,2 ,3 ,4 ,5 ]
Shi, Yiqin [1 ,2 ,3 ,4 ,5 ]
Ning, Yichun [1 ,2 ,3 ,4 ,5 ]
Hu, Jiachang [1 ,2 ,3 ,4 ,5 ]
Dai, Yan [1 ,2 ,3 ,4 ,5 ]
Ding, Xiaoqiang [1 ,2 ,3 ,4 ,5 ]
Zou, Jianzhou [1 ,2 ,3 ,4 ,5 ]
Teng, Jie [1 ,2 ,3 ,4 ,5 ]
机构
[1] Fudan Univ, Zhongshan Hosp, Div Nephrol, Shanghai, PR, Peoples R China
[2] Shanghai Med Ctr Kidney, Shanghai, Peoples R China
[3] Shanghai Inst Kidney & Dialysis, Shanghai, Peoples R China
[4] Shanghai Key Lab Kidney & Blood Purificat, Shanghai, Peoples R China
[5] Hemodialysis Qual Control Ctr Shanghai, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
HEPATOCYTE GROWTH-FACTOR; CELL-SURFACE PROTEOGLYCAN; FACTOR RECEPTOR; INTESTINAL INFLAMMATION; LEUKOCYTE RECRUITMENT; RENAL-FUNCTION; UP-REGULATION; LUNG INJURY; C-MET; APOPTOSIS;
D O I
10.1097/TP.0000000000002170
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background The hepatocyte growth factor (HGF) target pathway plays pivotal renoprotective roles after acute kidney injury. Syndecan-1 (SDC-1) serves as the coreceptor for HGF. Shedding of SDC-1 is involved in various pathological processes. Thus, we hypothesized that ischemia/reperfusion injury induced SDC-1 shedding, and inhibiting SDC-1 shedding would protect against kidney injury by potentiating activation of the HGF receptor mesenchymal epithelial transition factor (c-Met). Methods Expression of SDC-1 and its sheddases were observed in kidneys of sham and ischemia/reperfusion (I/R) mice. To inhibit SDC-1 shedding, mice were injected with the sheddase inhibitor GM6001 before I/R surgery, and then, renal inflammation, tubular apoptosis, and activation of the c-Met/AKT/glycogen synthase kinase-3 (GSK-3) pathway were analyzed. In vitro, human proximal tubular cell lines were pretreated with GM6001 under hypoxia/reperfusion conditions. The apoptosis and viability of cells and expression of c-Met/AKT/GSK-3 pathway components were evaluated. The relationship was further confirmed by treatment with SU11274, a specific inhibitor of phospho-c-Met. Results Shedding of SDC-1 was induced after ischemia/reperfusion injury both in vivo and in vitro. GM6001 pretreatment suppressed SDC-1 shedding, alleviated renal inflammation and tubular apoptosis, and upregulated phosphorylation of the c-Met/AKT/GSK-3 pathway. In vitro, pretreatment with GM6001 also decreased hypoxia/reperfusion-induced cell apoptosis and promoted activation of the c-Met pathway. In addition, the cytoprotective role of GM6001 was attenuated by suppressing c-Met phosphorylation with SU11274. Conclusions Our findings suggest that inhibiting I/R-induced SDC-1 shedding protected against ischemic acute kidney injury by potentiating the c-Met/AKT/GSK-3 pathway.
引用
收藏
页码:E331 / E344
页数:14
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