1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole and Reperfusion-Injury

Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

Topics: Allopurinol; Animals; Benzoates; Brain Death; Gene Expression; Hemodynamics; Imidazoles; Inflammation; Kidney; Kidney Transplantation; Lipid Peroxidation; Male; Nitrites; Rats; Rats, Inbred Lew; Reperfusion Injury; Signal Transduction; Sodium Nitrite

NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.

Topics: Animals; Benzoates; Hindlimb; Imidazoles; Ischemic Preconditioning; Liver; Liver Circulation; Male; Mice; Mice, Inbred C57BL; Microcirculation; Microscopy, Electron; Nitric Oxide; Reperfusion Injury; Signal Transduction; Transaminases

Hepatic IR (ischaemia/reperfusion) injury is an important clinical problem complicating liver surgery and transplantation. IPC (ischaemic preconditioning) is a strategy whereby brief episodes of IR in an organ can induce an adaptive response to protect against subsequent prolonged IR injury. However, trauma to vessels supplying the target organ is unavoidable using the technique of direct IPC. One amenable strategy would be to apply the protective preconditioning stimulus to an organ distant or remote from the target organ of interest, a technique known as RIPC (remote IPC). In the present issue of Clinical Science, Abu-Amara and co-workers utilize hindlimb RIPC as a novel therapeutic strategy against liver IR injury and investigate the mechanistic contribution of NO to hepatoprotection by administering C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt], an NO scavenger. Their experiments set the stage for more definitive studies to demonstrate a discernible benefit for the utility of RIPC in liver surgery and transplantation.

Topics: Animals; Benzoates; Hindlimb; Imidazoles; Ischemic Preconditioning; Liver; Mice; Nitric Oxide; Reperfusion Injury