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Stabilization of Cell-Cell Junctions Improves Outcomes in an Ex-Vivo Porcine Renal Ischemia-Reperfusion Injury Culture Model

L. Plumblee1, K. Patel2, L. Langerude3, Z. Tu3, D. Nord4, T. Beduschi3, S. Nadig5, C. Atkinson6

1MUSC College of Medicine, Gainesville, FL, 2University of Virgina, Charlottesville, VA, 3University of Florida, Gaineville, FL, 4Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, FL, 5Northwestern University, Charleston, SC, 6Pulmonary Medicine, University of Florida, Gainesville, FL

Meeting: 2022 American Transplant Congress

Abstract number: 948

Keywords: Donors, unrelated, Endothelial cells, Ischemia, Machine preservation

Topic: Basic Science » Basic Science » 15 - Machine Perfusion and Organ Rehabililtation - Basic

Session Information

Session Name: Machine Perfusion and Organ Rehabilitation - Basic

Session Type: Poster Abstract

Date: Sunday, June 5, 2022

Session Time: 7:00pm-8:00pm

 Presentation Time: 7:00pm-8:00pm

Location: Hynes Halls C & D

*Purpose: Renal transplant is an accepted therapy for end-stage renal failure. Chronic transplant dysfunction remains the leading cause of long-term graft loss and is, in part, caused by ischemia-reperfusion injury (IRI). Connexin proteins compromising cell-cell junctions, in particular Connexin43 (Cx43), govern many facets of endothelial cell functionality and play a pivotal role in the pathophysiology of IRI. We have developed and characterized a novel small molecule cell junction stabilizer, aCT1, which we have shown to improve endothelial integrity. Herein we explored the use of aCT1 as a pretreatment therapeutic to protect donor kidneys from the effects of IRI.

*Methods: Kidneys were harvested from 5 Yorkshire/Landrace pigs. Upon removal, kidneys were flushed with either HTK alone (n=6) or HTK supplemented with aCT1 (n=4). Kidneys were then cold stored for 36 hours prior to 6 hours of hypothermic pulsatile perfusion. On completion of perfusion 200 µm kidney sections were taken and organ cultures performed to simulate ex-vivo graft IRI. The effect of aCT1 therapy on machine perfusion dynamics, histopathology, and graft inflammation were analyzed in organ culture tissues.

*Results: aCT1 supplemention of HTK had no adverse effect on perfusion dynamics or kidney injury. Ex-vivo organ cultures demonstrated a significant increase in pro-inflammatory cytokines (IL-6, IL-8), adhesion molecules (P-selectin, ICAM, VCAM), and chemokine genes (MCP-1, IL-1β, TNF-α), key factors associated with IRI, which were all significantly reduced in aCT1 treated kidneys. Further, histological assessment of kidney sections demonstrated a significant reduction in tubular injury and the expression of KIM-1.

*Conclusions: Supplementation of standard of care HTK solution with cell junction modifying small molecule aCT1 significantly reduced ex-vivo kidney IRI and had no deleterious impact on graft performance during hypothermic pulsatile perfusion.

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To cite this abstract in AMA style:

Plumblee L, Patel K, Langerude L, Tu Z, Nord D, Beduschi T, Nadig S, Atkinson C. Stabilization of Cell-Cell Junctions Improves Outcomes in an Ex-Vivo Porcine Renal Ischemia-Reperfusion Injury Culture Model [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/stabilization-of-cell-cell-junctions-improves-outcomes-in-an-ex-vivo-porcine-renal-ischemia-reperfusion-injury-culture-model/. Accessed May 25, 2025.

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