RIPK3-mediated necroptosis promotes donor kidney inflammatory injury and reduces allograft survival.

Abstract

Kidney transplant injury occurs with ischemia and alloimmunity. Members of the receptor interacting protein kinase family (RIPK1,3) are key regulators of "necroptosis," a newly recognized, regulated form of necrosis. Necroptosis and apoptosis death appear to be counterbalanced as caspase-8 inhibition can divert death from apoptosis to necrosis. Inhibition of necroptosis in donor organs to limit injury has not been studied in transplant models. In this study, necroptosis was triggered in caspase inhibited tubular epithelial cells (TEC) exposed to tumor necrosis factor alpha in vitro, while RIPK1 inhibition with necrostatin-1 or use of RIPK3(-/-) TEC, prevented necroptosis. In vivo, short hairpin RNA silencing of caspase-8 in donor B6 mouse kidneys increased necroptosis, enhanced high-mobility group box 1 release, reduced renal function and accelerated rejection when transplanted into BALB/c recipients. Using ethidium homodimer perfusion to assess necrosis in vivo, necrosis was abrogated in RIPK3(-/-) kidneys postischemia. Following transplantation, recipients receiving RIPK3(-/-) kidneys had longer survival (p = 0.002) and improved renal function (p = 0.03) when compared to controls. In summary, we show for the first time that RIPK3-mediated necroptosis in donor kidneys can promote inflammatory injury, and has a major impact on renal ischemia-reperfusion injury and transplant survival. We suggest inhibition of necroptosis in donor organs may similarly provide a major clinical benefit.

• Authors: A Lau, S Wang, J Jiang, A Haig, A Pavlosky, A Linkermann, Z-X Zhang, A M Jevnikar
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 13 Issue 11 Pg. 2805-18 (Nov 2013) ISSN: 1600-6143 [Electronic] United States
• PMID: 24103001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• RNA, Messenger
• RNA, Small Interfering
• Tumor Necrosis Factors
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspase 8

Topics

• Allografts
• Animals
• Apoptosis
• Blotting, Western
• Caspase 8 (chemistry, genetics, metabolism)
• Graft Rejection (etiology, metabolism, pathology)
• Graft Survival
• Immunoenzyme Techniques
• Inflammation (etiology, metabolism, pathology)
• Kidney (injuries, metabolism, pathology)
• Kidney Transplantation
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Necrosis
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Receptor-Interacting Protein Serine-Threonine Kinases (physiology)
• Reperfusion Injury (genetics, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factors