Protective Effects of Sigma-1 Receptor Agonists in Renal Hypoxic Injury
Tóth Ákos Roland
Rácz Károly Konzervatív Orvostudományi Tagozat
Dr. Fekete Andrea
Semmelweis Egyetem I. sz. Gyermekgyógyászati Klinika Koós Aurél terem
2026-06-24 14:00:00
Gyermekkori betegségek klinikuma, élettana és prevenciója
Dr. Szabó Attila
Dr. Hosszú Ádám
Dr. Dobi Deján
Dr. Kun szilárd
Dr. Bödör Csaba
Dr. Ledó Nóra
Dr. Becs Gergely
CKD is a significant global health issue affecting over 850 million people worldwide and, in its advanced stages, is associated with progressive and ultimately complete loss of renal function. Importantly, IRI-caused AKI is increasingly recognized as a key risk factor for CKD. KTx remains the gold standard treatment for improving both survival and quality of life in patients with ESRD. Transplantation-related IRI is a complex pathophysiological process characterized by endothelial dysfunction, activation of cell death programs, and increased inflammation, which contribute to delayed graft function and adversely affect long-term transplant outcomes. Given the global shortage of donor organs, optimizing graft condition prior to transplantation is therefore of critical importance.
S1R is a multifunctional ligand-regulated chaperone protein. Previously, we described the precise localization of S1R in the kidney and demonstrated that S1R agonist fluvoxamine treatment improved postischemic survival and renal function by activating AKT–mediated NO signaling. Therefore, the main goal of our studies was to investigate whether supplementation of the preservation solution with S1R agonist FLU improves transplant outcomes. We further investigated a novel, low–BBB–penetrant S1R agonist, VCC904125, hypothesizing that it reduces apoptosis and inflammation to confer renoprotection.
In this study, we showed that pretransplant perfusion and storage of donor organs supplemented with an S1R agonist FLU significantly improves transplant outcomes through the reduction of functional impairment, tubular injury, inflammatory responses, and apoptosis. Furthermore, we developed a novel S1R agonist, VCC904125, with limited blood–brain barrier penetration and using murine models of renal ischemia–reperfusion injury and ex vivo CI, we demonstrated its renoprotective effects by targeting the key mechanisms underlying IRI pathology, apoptosis and inflammation.
These findings identify S1R activation as a promising strategy for improving graft preservation and potentially expanding the donor pool, although further studies are needed to confirm long-term benefits and clinical applicability.
8. References
