Sigma-1 Receptor Agonists are Renoprotective in Experimental Kidney Transplantation

A. Hosszu¹, T. Lakat¹, A. Toth¹, D. Balogh¹, J. Hodrea¹, L. J. Wagner², A. J. Szabo¹, A. Fekete¹

¹1st Department of Pediatrics, Semmelweis University, Budapest, Hungary, ²Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary

Meeting: 2021 American Transplant Congress

Abstract number: 601

Keywords: Kidney, Preservation solutions, Renal ischemia

Topic: Basic Science » Ischemia Reperfusion & Organ Rehabilitation

Session Information

Session Name: Ischemia Reperfusion & Organ Rehabilitation

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*Purpose: Kidney transplantation (Tx) is associated with better quality of life and reduced costs compared to dialysis, but the shortage in donor organs is a limiting factor. Graft survival is highly dependent on the extent of ischemia/reperfusion injury (IRI) during Tx. We recently described the renoprotective effects of Sigma-1 receptor (S1R) agonist treatment in renal IRI. Thus, our aim was to develop a preservation solution which minimizes ischemic graft damage in order to improve Tx outcomes and 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; (iii) SA-4503 or (iv) VCC compound for 2 hours, then autotransplanted and sacrificed 24 hours or 9 days after reperfusion. Sham-operated rats served as controls. In a second experiment kidneys wild-type and S1R knockout mice were perfused and placed in ice cold Custodiol or Custodiol containing various selective S1R agonists for 2/3/8/24 hours of cold ischemia and tissue samples were collected for histological evaluation.

*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, decreased apoptotic Bax expression, while increased anti-apoptotic Bcl2 expression. Reduced number of CD45+ leukocytes and reduced inflammatory cytokine (Mcp1, Il1a, Il6, Tnf) expressions confirmed the anti-inflammatory effect of S1R agonists. All S1R agonists mitigated cold ischemic structural kidney damage at all time points.

*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: 2017-1.3.1-VKE-2017-00006; OTKA PD-131637; FK-124491; 2020-4.1.1.-TKP2020-6183069269; 2020-4.1.1.-TKP2020–6183169273; ÚNKP-20-4-II-SE-13

To cite this abstract in AMA style:

Hosszu A, Lakat T, Toth A, Balogh D, Hodrea J, Wagner LJ, Szabo AJ, Fekete A. Sigma-1 Receptor Agonists are Renoprotective in Experimental Kidney Transplantation [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/sigma-1-receptor-agonists-are-renoprotective-in-experimental-kidney-transplantation/. Accessed May 30, 2025.

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