PhD Scientific Days 2021

Budapest, 7-8 July 2021

TT_II_P: Theoretical and Translational Medicine II. Posters

Sigma-1 Receptor Agonists Are Renoprotective in Experimental Kidney Transplantation

Ádám Hosszú1,2; Tamás Lakat,1,2; Ákos Tóth1,2; Judit Hodrea1, 2; László J. Wagner3; Attila J. Szabó2; Andrea Fekete1,2

1 SE Diabetes Research Group, Budapest, Hungary
2 Semmelweis University 1st Department of Pediatrics, Budapest, Hungary
3 Semmelweis University Department of Transplantation and Surgery, Budapest, Hungary

Text of the abstract

Introduction:
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.

Aims:
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; 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 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.

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.

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:
ÚNKP-20-4-II-SE-13; OTKA PD-131637; FK-124491; 2020-4.1.1.-TKP2020-6183069269; 2020-4.1.1.-TKP2020-6183169273;

University and Doctoral School

Semmelweis University, Károly Rácz Doctoral School of Clinical Medicine