BACKGROUND: In clinical transplantation, ischemia-reperfusion injury (I/RI) causes damage to DNA. We hypothesize that one form of damage is the demethylation of methylated cytosines in the donor genome caused by the oxidative environment created first by ischemia, and subsequently by reperfusion on transplantation. This study contributes to the understanding of how the short-lived and transient ischemic insult may influence chronic pathological changes that occur in clinical transplantation in the long term. METHODS: A model of I/RI and chronic rejection; Fisher to Fisher kidney transplant rendered cold-ischemic for 4 hr before transplantation, to induce antigen-independent chronic nephropathy over a 6-month period, was used. Tissue was assessed by histopathology and methylation by pyrosequencing analysis. RESULTS: An epigenetic map of the rat renal C3 promoter was produced, which identified methylated Cytosine phospho Guanine (CpG) sites coincident to cytokine response elements and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) binding sites. Pyrosequencing analysis showed that the tissue that had undergone 4 hr ischemia and reperfusion developed aberrant demethylation of cytosines in putative regulatory sites within the C3 promoter. CONCLUSION: These findings may describe a newly recognized phenomena in the field of transplantation. Aberrant demethylation has long been linked to the development of tumors, and our data suggest a similar mechanism of gene dysregulation that may be initiated by I/RI with acute and chronic effects. These data may contribute to a further understanding of how the short lived and transient ischemic insult influences chronic pathological changes that occur even in the absence of major histocompatibility complex disparity in transplantation.
BACKGROUND: In clinical transplantation, ischemia-reperfusion injury (I/RI) causes damage to DNA. We hypothesize that one form of damage is the demethylation of methylated cytosines in the donor genome caused by the oxidative environment created first by ischemia, and subsequently by reperfusion on transplantation. This study contributes to the understanding of how the short-lived and transient ischemic insult may influence chronic pathological changes that occur in clinical transplantation in the long term. METHODS: A model of I/RI and chronic rejection; Fisher to Fisher kidney transplant rendered cold-ischemic for 4 hr before transplantation, to induce antigen-independent chronic nephropathy over a 6-month period, was used. Tissue was assessed by histopathology and methylation by pyrosequencing analysis. RESULTS: An epigenetic map of the rat renal C3 promoter was produced, which identified methylated Cytosine phospho Guanine (CpG) sites coincident to cytokine response elements and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) binding sites. Pyrosequencing analysis showed that the tissue that had undergone 4 hr ischemia and reperfusion developed aberrant demethylation of cytosines in putative regulatory sites within the C3 promoter. CONCLUSION: These findings may describe a newly recognized phenomena in the field of transplantation. Aberrant demethylation has long been linked to the development of tumors, and our data suggest a similar mechanism of gene dysregulation that may be initiated by I/RI with acute and chronic effects. These data may contribute to a further understanding of how the short lived and transient ischemic insult influences chronic pathological changes that occur even in the absence of major histocompatibility complex disparity in transplantation.
Authors: Diego Mastroeni; Andrew Grover; Elaine Delvaux; Charisse Whiteside; Paul D Coleman; Joseph Rogers Journal: Neurobiol Aging Date: 2011-04-11 Impact factor: 4.673
Authors: S V Bontha; D G Maluf; K J Archer; C I Dumur; M G Dozmorov; A L King; E Akalin; T F Mueller; L Gallon; V R Mas Journal: Am J Transplant Date: 2017-07-08 Impact factor: 8.086
Authors: R J Shah; S L Bellamy; J C Lee; E Cantu; J M Diamond; N Mangalmurti; S M Kawut; L B Ware; J D Christie Journal: Am J Transplant Date: 2013-01-17 Impact factor: 8.086