Syndecan-1 shedding inhibition to protect against ischemic acute kidney injury through HGF target signaling pathway

Background The hepatocyte growth factor (HGF) target pathway plays pivotal renoprotective roles after acute kidney injury (AKI). Syndecan-1 serves as the co-receptor for HGF. Shedding of syndecan-1 is involved in various pathological processes. Thus, we hypothesized that IRI induced syndecan-1 shedding and inhibiting syndecan-1 shedding would protect against kidney injury by potentiating activation of the HGF receptor c-Met. Methods Expression of syndecan-1 and its sheddases were observed in kidneys of sham and I/R mice. To inhibit syndecan-1 shedding, mice were injected with the sheddase inhibitor GM6001 prior to I/R surgery, and then, renal inflammation, tubular apoptosis and activation of the c-Met/AKT/GSK-3β pathway were analysed. In vitro, HK-2 cells were pretreated with GM6001 under hypoxia/reperfusion (H/R) conditions. The apoptosis and viability of cells and expression of c-Met/AKT/GSK-3β pathway components were evaluated. The relationship was further confirmed by treatment with SU11274, a specific inhibitor of phospho-c-Met. Results Shedding of syndecan-1 was induced after IRI both in vivo and in vitro. GM6001 pretreatment suppressed syndecan-1 shedding, and alleviated renal inflammation and tubular apoptosis, and upregulated phosphorylation of the c-Met/AKT/GSK-3β pathway. In vitro, pretreatment with GM6001 also decreased H/R-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. Conclusion Our findings suggest that inhibiting I/R-induced syndecan-1 shedding protected against ischaemic acute kidney injury by potentiating the c-Met/AKT/GSK-3β pathway. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. # Co-first authors, these authors contributed equally to this work. Corresponding author: Jianzhou Zou and Jie Teng, Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, PR China. Fax: +86-021-64038038. Telephone: +86-021-64041990. Email: zou.jianzhou@zs-hospital.sh.cn and teng.jie@zs-hospital.sh.cn Author Contributions Z.L. and N.S. conceived the study, performed the experiment, generated figures and wrote the manuscript. B.S., X.X., J.H., Y.N. performed the experiment and collected data. Y.F., Y.S and Y.D. searched literature and analyzed data. X.D. revised the manuscript. J.Z. and T.J. desigend the study, interpreted data and revised the manuscript. Conflict of interest All the authors declared no conflicts of interest. Fundings This work was funded by National Natural Science Foundation of China (81500048, 81430015 and 81670614), Talent Development Program of Zhongshan Hospital-Outstanding Backbone Project (2017ZSGG19) and Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai Science and Technology Commission (14DZ2260200). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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