Abstract
Clinical evidence has indicated a possible link between renal injury and remote liver injury. We investigated whether extracellular histone mediates remote hepatic damage after renal graft ischemia–reperfusion injury, while vascular endothelial growth factor (VEGF) is protective against remote hepatic injury. In vitro, hepatocyte HepG2 cultures were treated with histone. In vivo, the Brown‐Norway renal graft was stored in 4°C preservation solution for 24 hours and then transplanted into a Lewis rat recipient; blood samples and livers from recipients were harvested 24 hours after surgery. Prolonged cold ischemia in renal grafts enhanced liver injury 24 hours after engraftment. Caspase‐1, ASC, NLRP3, and AIM2 expressions in hepatocyte, CD68+‐infiltrating macrophages, tissue, and serum interleukin‐1β and ‐18 were greatly elevated, indicating that pyroptosis occurred in the liver and resulted in acute liver functional impairment. Blocking the caspase‐1 pathway decreased the number of necrotic hepatocytes. VEGF treatment suppressed the hepatocyte pyroptosis and liver function was partially restored. Our data suggested that renal allograft ischemia–reperfusion injury is likely associated with acute liver damage due to hepatocyte pyroptosis induced by histone and such injury may be protected by VEGF administration. VEGF, therefore, may serve as a new strategy against other remote organ injuries related to renal transplantation.
Highlights
Ischemia–reperfusion injury (IRI) is an inevitable consequence of renal transplantation and a major determinant of graft survival
Activation of the hypoxia inducible factor (HIF)-vascular endothelial growth factor (VEGF) system (Figure 3I) was noted, associated with an enhanced expression of VEGF (Figure 3J) by 5-fold compared with naive controls, with ELISA demonstrating an increased expression of VEGF in both liver tissue and serum (Figure 3K,L). These findings indicate the oligomerization of NLRP and absent in melanoma 2 (AIM2), formation of the NLRP3 and AIM2 inflammasomes, and subsequent recruitment of Apoptosis-associated speck-like protein containing a CARD (ASC) and pro–caspase-1, resulting in an increase in hepatic pyroptosis in remote hepatic injury, while activation of the HIF-VEGF system occurs after renal graft transplantation
We demonstrated for the first time the progressive increase in histone release and induced pyroptosis during remote hepatic injury in a rat model of renal allograft transplantation
Summary
Ischemia–reperfusion injury (IRI) is an inevitable consequence of renal transplantation and a major determinant of graft survival. Remote hepatic injury is believed to be initiated and sustained by proinflammatory cytokines that are released or activated during IRI after renal damage.[8,9] If liver repair and regenerative mechanism are not activated promptly, acute liver functional impairment could occur. Clinical management of such patients is difficult, and effective organ protective strategy is required. The underlying molecular mechanism, which is centered on pyroptosis, was explored in this study
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