Sigma-1 Receptor Agonists Are Protective in a Rat Model of Kidney Transplantation
11st Department of Pediatrics, Semmelweis University, Budapest, Hungary, 2Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
Meeting: 2022 American Transplant Congress
Abstract number: 362
Keywords: Ischemia, Kidney, Preservation solutions
Topic: Basic Science » Basic Science » 15 - Machine Perfusion and Organ Rehabililtation - Basic
Session Information
Session Name: Machine Perfusion and Organ Rehabililtation - Basic
Session Type: Rapid Fire Oral Abstract
Date: Monday, June 6, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 5:50pm-6:00pm
Location: Hynes Ballroom A
*Purpose: Kidney transplantation (Tx) is associated with better long-term outcomes and quality of life compared to dialysis, but the shortage in donor organs is 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 which, with the addition of S1R agonist compounds, minimizes ischemic damage in order to improve the condition of grafts and so to increase the number of organs suitable for Tx.
*Methods: 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 hours, then autotransplanted and sacrificed 24 hours 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 ice cold preservation solution containing an original, selective S1R agonist compound (VCC) for 24 hours of cold ischemia and tissue samples were collected.
*Results: S1R agonists mitigated renal functional impairment and tubular dilatation following Tx. Expression of early and sensitive tubular injury markers Kim1 and Ngal were markedly less elevated in S1R agonist-treated kidneys. S1R agonists alleviated renal apoptosis as shown on TUNEL-stained kidney sections. Reduced number of CD45+ leukocytes and reduced inflammatory cytokine (Mcp1, Il1a, Il6, Tnf) expressions confirmed the anti-inflammatory effect of S1R agonists. The S1R agonist VCC compound mitigated cold ischemic structural kidney damage and apoptosis in wild-type, but not in S1R KO mice, which confirms the protective role of the receptor.
*Conclusions: 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-131637; FK-124491; 2020-4.1.1.-TKP2020-6183069269; 2020-4.1.1.-TKP2020–6183169273; KDP-2020/1019145
To cite this abstract in AMA style:
Hosszu A, Lakat T, Toth A, Hodrea J, Wagner L, Szabo AJ, Fekete A. Sigma-1 Receptor Agonists Are Protective in a Rat Model of Kidney Transplantation [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/sigma-1-receptor-agonists-are-protective-in-a-rat-model-of-kidney-transplantation/. Accessed May 17, 2025.« Back to 2022 American Transplant Congress