MO1019: Sigma-1 Receptor Agonists are Protective in a Rat Model of Kidney Transplantation

Abstract

Abstract BACKGROUND AND AIMS End-stage renal disease affects nearly 2 million people worldwide. The disease is associated with an irreversible deterioration in renal function and can only be treated by dialysis or kidney transplantation (KTx). KTx is associated with better long-term outcomes and quality of life compared with dialysis, but the shortage of donor organs is a serious and unsolved problem. Graft survival is highly dependent on the extent of cold and warm ischemic injury during Tx. We recently described the renoprotective effects of Sigma-1 receptor (S1R) agonist treatment in IRI. Thus, our aim was to develop a novel preservation solution that, with the addition of S1R agonist compounds, minimizes ischemic damage in order to improve the condition of grafts and so increase the number of organs suitable for Tx. METHOD Kidneys of male Wistar rats were perfused and placed in ice cold (i) custodiol preservation solution; custodiol containing S1R agonists, (ii) fluvoxamine or (iii) SA-4503 for 2 h, then autotransplanted and sacrificed 24 h after reperfusion. Sham-operated rats served as controls. In a second experiment, kidneys of wild-type and S1R knockout mice were perfused and placed in an ice-cold preservation solution containing an original, selective S1R agonist compound (VCC) for 24 h of cold ischemia and tissue samples were collected. Renal function parameters were determined. Renal expression of tubular injury markers (Kim-1, Ngal) and inflammatory cytokines (Il-1α, Il-6, Tnf-α, Mcp-1) were measured. Periodic acid-Schiff staining was performed on kidney tissue sections to evaluate structural changes. CD45 immunostaining was performed on kidney sections to determine the extent of leukocyte infiltration. DNA fragmentation resulted by apoptotic events in the kidney was evaluated by TUNEL-assay. RESULTS S1R agonists mitigated renal functional impairment and tubular dilatation following Tx. Expression of early and sensitive tubular injury markers was markedly less elevated in S1R agonist-treated kidneys. S1R agonists alleviated renal apoptosis as shown on TUNEL-stained kidney sections. Decreased numbers of CD45 + leukocytes and decreased inflammatory cytokine expressions confirmed the anti-inflammatory effect of S1R agonists. The S1R agonist VCC compound mitigated cold ischemic structural kidney damage in wild-type but not in S1R KO mice, which confirms the protective role of the receptor. CONCLUSION The addition of S1R agonists to the preservation solution during Tx improves graft function and alleviates structural damage, thus improving long-term outcomes. S1R agonists reduce graft injury during cold storage, therefore the number of transplantable donor organs can be increased. FUNDING OTKA PD-131 637; FK-124 491; 2020–4.1.1.-TKP2020-6 183 069 269; 2020–4.1.1.-TKP2020-6 183 169 273; KDP-2020/1 019 145.