Ian Lobb1, Michael Davison2, David Carter3, Weihua Liu4, Aaron Haig4, Lakshman Gunaratnam5, Alp Sener6. 1. Department of Microbiology and Immunology, London Health Sciences Center, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada. 2. Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada. 3. Research Institute, London Health Sciences Center, Western University, London, Ontario, Canada. 4. Department of Pathology, London Health Sciences Center, Western University, London, Ontario, Canada. 5. Department of Microbiology and Immunology, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, Ontario, Canada; Department of Medicine, London Health Sciences Center, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada. 6. Department of Microbiology and Immunology, London Health Sciences Center, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada. Electronic address: alp.Sener@lhsc.on.ca.
Abstract
PURPOSE: Ischemia-reperfusion injury is unavoidable during organ transplantation. Prolonged ischemia-reperfusion injury is detrimental to short-term and long-term graft function and survival. H2S is a recently characterized, endogenously produced gaseous molecule with important physiological roles that has been shown to be cytoprotective during tissue ischemia-reperfusion injury. The current study aimed to determine whether H2S could mitigate cold renal ischemia-reperfusion injury in the clinically relevant context of allogeneic renal transplantation. MATERIALS AND METHODS: Following bilateral native nephrectomy Lewis rats underwent renal transplantation with kidneys from Brown Norway donor rats that were flushed with cold (4C) standard University of Wisconsin preservation solution (University of Wisconsin preservation solution group) or cold University of Wisconsin preservation solution plus 150 μM NaHS (H2S group) solution. Kidneys were stored for 6 hours at 4C in the same solution. Recipient animals were monitored for 14 days or until sacrifice using metabolic cages to assess various parameters of renal graft function. RESULTS: H2S treatment improved early allograft survival and function, and decreased early levels of necrosis, apoptosis and Kim-1 compared to University of Wisconsin preservation solution alone. H2S treatment did not affect allograft rejection. Rather, it modulated the early allograft transcriptome to decrease the expression of renal injury, coagulation and cellular stress response genes, and increase the expression of cellular proliferation and Ifn-γ induced genes compared to University of Wisconsin preservation solution alone. CONCLUSIONS: To our knowledge our findings are the first to show that H2S protects donor kidneys against cold ischemia-reperfusion injury in the context of allogeneic renal transplantation. This potentially represents a novel cost-effective therapeutic solution to mitigate ischemia-reperfusion injury and improve the clinical outcomes of renal transplantation.
PURPOSE:Ischemia-reperfusion injury is unavoidable during organ transplantation. Prolonged ischemia-reperfusion injury is detrimental to short-term and long-term graft function and survival. H2S is a recently characterized, endogenously produced gaseous molecule with important physiological roles that has been shown to be cytoprotective during tissue ischemia-reperfusion injury. The current study aimed to determine whether H2S could mitigate cold renal ischemia-reperfusion injury in the clinically relevant context of allogeneic renal transplantation. MATERIALS AND METHODS: Following bilateral native nephrectomy Lewis rats underwent renal transplantation with kidneys from Brown Norway donorrats that were flushed with cold (4C) standard University of Wisconsin preservation solution (University of Wisconsin preservation solution group) or cold University of Wisconsin preservation solution plus 150 μM NaHS (H2S group) solution. Kidneys were stored for 6 hours at 4C in the same solution. Recipient animals were monitored for 14 days or until sacrifice using metabolic cages to assess various parameters of renal graft function. RESULTS:H2S treatment improved early allograft survival and function, and decreased early levels of necrosis, apoptosis and Kim-1 compared to University of Wisconsin preservation solution alone. H2S treatment did not affect allograft rejection. Rather, it modulated the early allograft transcriptome to decrease the expression of renal injury, coagulation and cellular stress response genes, and increase the expression of cellular proliferation and Ifn-γ induced genes compared to University of Wisconsin preservation solution alone. CONCLUSIONS: To our knowledge our findings are the first to show that H2S protects donor kidneys against cold ischemia-reperfusion injury in the context of allogeneic renal transplantation. This potentially represents a novel cost-effective therapeutic solution to mitigate ischemia-reperfusion injury and improve the clinical outcomes of renal transplantation.
Authors: Smriti Juriasingani; Ashley Jackson; Max Yulin Zhang; Aushanth Ruthirakanthan; George J Dugbartey; Emrullah Sogutdelen; Max Levine; Moaath Mandurah; Matthew Whiteman; Patrick Luke; Alp Sener Journal: Int J Mol Sci Date: 2021-07-02 Impact factor: 5.923