Sigma-1 Receptor Agonists Are Renoprotective in a Rat Model of Kidney Transplantation

A. Hosszu¹, Z. Antal², L. Illesy², L. Lenart¹, D. B. Balogh¹, L. Wagner³, A. Vannay⁴, A. J. Szabo², A. Fekete¹

¹"Lendulet" Diabetes Research Group, MTA-SE, Budapest, Hungary, ²1st Department of Pediatrics, Semmelweis University, Budapest, Hungary, ³Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary, ⁴Pediatrics and Nephrology Research Group, MTA-SE, Budapest, Hungary

Meeting: 2019 American Transplant Congress

Abstract number: A89

Keywords: Apoptosis, Inflammation, Ischemia, Preservation solutions

Session Information

Session Name: Poster Session A: Ischemia Reperfusion & Organ Rehabilition

Session Type: Poster Session

Date: Saturday, June 1, 2019

Session Time: 5:30pm-7:30pm

Presentation Time: 5:30pm-7:30pm

Location: Hall C & D

*Purpose: Kidney transplantation 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 transplantation. We were the first to describe the renoprotective effects of Sigma-1 receptor (S1R) agonist treatment in renal IRI. Our aim was to develop a preservation solution, which with the addition of a S1R agonist compound minimizes ischemic graft damage in order to improve transplantation outcomes and to increase the number of organs suitable for transplantation.

*Methods: Kidneys of male Wistar rats were perfused and placed in ice cold (i) Custodiol preservation solution; Custodiol containing selective 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 were perfused and placed in ice cold Custodiol or Custodiol containing various selective S1R agonists for 2/3/8/24 hours and tissue samples were collected.

*Results: S1R agonists mitigated renal functional impairment and tubular dilatation following transplantation. 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 and increased anti-apoptotic Bcl2 expression. Reduced number of CD45+ leukocytes and inflammatory cytokine (Mcp1, Il1a, Il6, Tnf) expression 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 kidney transplantation 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: LP008/2017; VKE-2017-00006; OTKA FK-124491; K-116928; K-112629; NN-114607; EEMOFÁKT-2017

To cite this abstract in AMA style:

Hosszu A, Antal Z, Illesy L, Lenart L, Balogh DB, Wagner L, Vannay A, Szabo AJ, Fekete A. Sigma-1 Receptor Agonists Are Renoprotective in a Rat Model of Kidney Transplantation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/sigma-1-receptor-agonists-are-renoprotective-in-a-rat-model-of-kidney-transplantation/. Accessed May 9, 2025.

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