12-hydroxy-5-8-10-14-eicosatetraenoic-acid and Ischemia

Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females.. 13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography-mass spectrometry (LC/MS).. Male SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR.. Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Kidney Injury; Animals; Arachidonate 15-Lipoxygenase; Female; Inflammation; Ischemia; Kidney; Male; Rats; Rats, Inbred SHR; Reperfusion Injury

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonate 12-Lipoxygenase; Humans; Ischemia; Liver; Receptors, G-Protein-Coupled; Reperfusion Injury; Signal Transduction

The role of nitric oxide in lipoxygenase metabolism after a process of ischemia-reperfusion in pancreas transplantation has been evaluated in this study. Sprague-Dawley rats were randomized into three groups, as follows: Group I--Control animals not surgically manipulated; Group II.--Pancreas transplantation, after 12 h of organ preservation; Group III.--Same as II but with administration of NG-nitro-L-arginine methyl esther (a nitric oxide synthase inhibitor) (10 mg/Kg) prior to organ revascularization. The results show post-transplantation increases in leukotriene B4 and 12-hydroxyeicosatraenoic acid levels in pancreatic tissue. Nitric oxide synthase inhibition reversed the increases in 12-hydroxyeicosatetraenoic acid, but was unable to modify leukotriene B4 increases suggesting the existence of a direct effect of nitric oxide on the 12-lipoxygenase metabolism in pancreas transplantation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Animals; Arachidonate 12-Lipoxygenase; Enzyme Activation; Enzyme Inhibitors; Free Radicals; Gene Expression Regulation; Ischemia; Leukotriene B4; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Organ Preservation; Pancreas; Pancreas Transplantation; Pancreatitis; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The implication of eicosanoid metabolism and its relationship with oxygen free radical production in the process of ischemia-reperfusion associated with rat pancreas transplantation has been explored in this study. For this purpose male Sprague-Dawley rats were classified as follows: group I, control animals not surgically manipulated; group II, pancreas transplantation, after 30 min preservation in UW solution; group III, pancreas transplantation after 12 h preservation under the same conditions; group IV, same as group III but with administration of SOD 5 min prior to organ revascularization. The results show post-transplantation increases in 6-keto-PGF1 alpha, TXB2, LTB4 and 12-HETE in pancreatic tissue independent of preservation time. The fact that SOD administration could reverse these increases even though an efficient xanthine oxidase irreversible inhibitor such as allopurinol was present in the preservation solution suggests that eicosanoid generation in the recipient rat would be mediated by an oxygen free radical dependent mechanism not exclusively dependent on endothelial xanthine oxidase activity.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Cold Temperature; Free Radicals; Hydroxyeicosatetraenoic Acids; Ischemia; Leukotriene B4; Male; Organ Preservation; Pancreas; Pancreas Transplantation; Rats; Rats, Sprague-Dawley; Reperfusion; Superoxide Dismutase; Thromboxane B2