Sigma‐1 Receptor Agonists Are Renoprotective in Experimental Kidney Transplantation

Abstract

Introduction and aimsKidney 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.MethodsKidneys 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 rats as well as 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 and tissue samples were collected.ResultsS1R 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.ConclusionThe 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.Support or Funding InformationGrants: VKE‐2017‐00006; OTKA PD‐131637; FK‐124491; K‐116928; NN‐114607; FIKP; STIA_18_KF