During systemic stress, syndecan-1 (SDC-1) shedding into plasma results, implying endothelial damage. RBT-1, a "preconditioning" agent, has been shown to mitigate postoperative complications following cardiac surgeries. This study assessed whether RBT-1 preconditioning attenuated SDC-1 shedding in these patients, implying a vascular protective effect. Patients (n, 112) were randomized to receive low-dose RBT-1, high-dose RBT-1, or placebo 24-48 h prior to surgery. Plasma samples were obtained before and 2 days postsurgery and assayed for SDC-1 (ELISA). To gain further insights, male CD-1 mice were subjected to acute renal injuries, and RBT-1's impact on plasma SDC-1 increases, vascular/aortic stress responses (NGAL/KIM-1/IL-6 gene induction), and two vascular cytoprotective pathways (Nrf2; ferritin) were assessed. Baseline plasma SDC-1 levels did not differ between patient groups. The placebo group developed an approximate 50% plasma SDC-1 (ng/mL) increase (p, 0.012). Conversely, no significant SDC-1 increases were seen in the RBT-1 treatment groups. Experimental injury markedly increased plasma SDC-1 concentrations, and these were significantly blunted by RBT-1 preconditioning. RBT-1 also mitigated AKI-induced aortic NGAL/KIM-1/IL-6 mRNA increases, activated aortic Nrf2, and increased vascular ferritin levels. RBT-1 preconditioning diminishes SDC-1 release and upregulates vascular ferritin and Nrf2. Hence, RBT-1 preconditioning can confer select vasoprotective effects.