RBT-1, A Pro-Oxidant Preconditioning Agent, Mitigates Syndecan-1 Shedding in Patients Undergoing Cardiac Surgery and Following Experimental AKI

Background: During systemic stress, e.g., sepsis or major surgeries, syndecan-1 (SDC-1) shedding into plasma results, imply endothelial glycocalyx damage. A recent phase 2 clinical trial indicated that RBT-1 induced ‘oxidant preconditioning’ mitigated post-operative complications following cardiac surgeries. The present study assessed whether RBT-1 preconditioning attenuated SDC-1 shedding in these patients, implying a vascular protective effect. Methods: Patients (n, 112) were randomized to receive low-dose RBT-1, high-dose RBT-1, or placebo 24-48 hrs prior to surgery. Plasma samples were obtained before and 2 days post-surgery and assayed for SDC-1 (ELISA). The results were compared between the groups. To gain further insights, CD-1 mice were subjected to diverse forms of acute renal injuries (maleate, glycerol, endotoxemic AKI; acute heart failure). RBT-1’s impact on resulting plasma SDC-1 increases, vascular/aortic stress (NGAL/IL-6 gene induction), and the expression of two vascular cytoprotective pathways (Nrf2; ferritin) were assessed. Results: Baseline plasma SDC-1 levels did not differ between the three patient groups. The placebo group developed a 40 ± 11% post-surgical plasma SDC-1 increase (p, 0.03). Conversely, no significant SDC-1 increases (< 10%) were observed in the RBT-1 treatment groups (< RBT-1 vs. placebos, p, 0.015). Each form of experimental injury markedly increased plasma SDC concentrations. This result was attenuated by RBT-1 preconditioning. RBT-1 also: i) Mitigated injury-induced aortic NGAL/IL-6 mRNA increases; ii) Activated aortic Nrf2; and iii) Increased ferritin expression in aorta and select renal vessels. Conclusion: RBT-1 induced ‘oxidant preconditioning’ confers a vaso-protective effect, potentially by activating Nrf2 and up-regulating ferritin. Whether this can decrease post-cardiac surgery complications requires further study.