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. 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.