leukotriene-b4 and Kidney-Diseases

Lipoxygenase products are synthesized in the kidney. Rabbit medulla and murine and human glomeruli produce 12- and 15-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE). Minor amounts of leukotrienes are formed under normal conditions, but it is likely that the resident renal cells are capable of synthesizing these metabolites. Rat glomeruli and papillae possess the enzymes necessary to process leukotriene C4 into leukotrienes D4 and E4. However, the enzyme activity of the papillae is masked due to the presence of an inhibitor detected in the 10,000 g supernate of the papillary homogenate. 12-HETE synthesis is markedly increased in glomeruli from rats with nephrotoxic serum nephritis and leukotriene B4 synthesis in glomeruli from rats with cationic bovine gamma-globulin-induced glomerulonephritis. In vivo consequences of the association between the resident glomerular cells and the bone marrow-derived cells have been studied in vitro in co-incubation experiments. Glomeruli release factors that stimulate the cyclo-oxygenase and lipoxygenase pathways in macrophages. Co-incubation of glomeruli, platelets, and polymorphonuclear leukocytes results in the formation of 12,20-diHETE and an excess of 12-HETE. Lipoxygenase products, regardless of their origin, modify the renal functions. Leukotriene C4 binds specifically to rat glomeruli and human cultured glomerular epithelial cells. Leukotrienes C4 or D4 administered in vivo cause renal vasoconstriction and a decline in the glomerular filtration rate. In vitro, these two sulfidopeptide leukotrienes promote epithelial cell proliferation and produce mesangial cell contraction. The lipoxygenase pathway is also implicated in the attachment of macrophages to glomeruli and in the oxidative burst of glomerular mesangial cells during phagocytosis. The future use of specific inhibitors of the synthesis or antagonists of the lipoxygenase products, particularly the leukotrienes, should provide a tool for evaluating the role of these metabolites in renal diseases.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Humans; Hydroxyeicosatetraenoic Acids; Kidney; Kidney Diseases; Leukotriene B4; Lipoxygenase; SRS-A

The present study examined the possible involvement of the lipoxygenase (LOX) pathway in cisplatin (CPT)-induced nephrotoxicity.. Wistar albino rats were challenged with CPT IP injection (7.5 mg/kg) and were sacrificed after one week. Signs of renal dysfunction, including urea and creatinine clearance levels and renal histological structure, were investigated. Gene and protein expression levels of different LOX pathway enzymes and products, including 5-LOX, 12-LOX, 15-LOX, 5-LOX activating protein (FLAP), leukotriene A4 hydrolase (LTA4 hydrolase), leukotriene C4 synthase (LTC4 synthase), LTB4 receptor, and cysteinyl (cys) LT receptor types 1 and 2, were also determined in the kidneys using real-time PCR and western blotting, respectively. The serum and kidney levels of LTB4 and inflammatory markers were also estimated.. CPT renal toxicity was established as the creatinine and urea clearance levels were significantly reduced, while the serum levels of creatinine and urea were markedly increased. We reported a considerable up-regulation in the mRNA and protein expression levels of 5-LOX, FLAP, 12-LOX, LTA4 hydrolase, LTC4 synthase, LTB4 receptor, and Cys LT receptor types 1 and 2, while 15-LOX expression did not significantly change in the CPT group. Additionally, LTB4 and inflammatory indicators in serum and renal levels were elevated significantly in the CPT group. Histopathological examination clearly showed the nephrotoxic changes in the renal tissues of CPT-challenged animals.. Our findings suggested, for the first time, the participation of LOX enzymes and products in the signaling pathway leading to CPT-associated nephrotoxicity, which could be the foundation stone for combining LOX pathway attenuators with CPT therapy to decrease CPT-associated renal toxicity.

Topics: Animals; Blotting, Western; Cisplatin; Creatinine; Gene Expression Regulation; Kidney Diseases; Kidney Function Tests; Leukotriene B4; Leukotrienes; Lipoxygenase; Male; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

Glomerular infiltration of macrophages is a characteristic alteration of renal pathology in hyperlipidaemic renal injury. Leukotriene B4 (LTB4) is a bioactive eicosanoid and macrophage and has two key enzymes for LTB4 synthesis, 5-lipoxygenase and leukotriene A4 (LTA4) hydrolase. The purpose of this study was to evaluate the role of LTB4 in accelerated hyperlipidaemic renal injury.. To induce accelerated hyperlipidaemic renal injury, 8 week old male spontaneously hypercholesterolaemic (SHC) rats were fed with a high cholesterol diet for 6 weeks. LTA4 hydrolase activities in the kidney and urine LTB4 levels were examined. The effects of LTB4 antagonist (ONO-4057) were also evaluated.. Urinary protein and LTB4 excretion was increased by a high cholesterol diet for 6 weeks. The scores of glomerular foam cell accumulation and sclerosis, numbers of infiltrated macrophages in glomeruli and interstitial area, LTA4 hydrolase activity in renal cortex were higher in the high cholesterol diet group than the normal diet group. LTB4 antagonist treatment reduced urinary protein and LTA4 activity and attenuated renal pathological changes.. These results suggest that LTB4 directly contributes to accelerated hyperlipidaemic renal injury and the therapeutic potential of LTB4 antagonist for renal damage induced by hyperlipidaemia.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Epoxide Hydrolases; Foam Cells; Hypercholesterolemia; Kidney Diseases; Kidney Glomerulus; Leukotriene Antagonists; Leukotriene B4; Male; Phenylpropionates; Proteinuria; Rats; Time Factors

We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury.. Three groups of Sprague-Dawley rats (n=16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n=4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-β expression, apoptosis, and tissue levels of arachidonic acid, MIP-1α, IL-1β, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue.. Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury.

Topics: Analysis of Variance; Animals; Apoptosis; Arachidonic Acid; Chemokine CCL2; Chemokine CCL3; Collagen; Dietary Fats, Unsaturated; Dietary Supplements; Fibrosis; Fish Oils; Heme Oxygenase-1; Inflammation; Interleukin-1beta; Kidney Diseases; Leukotriene B4; Macrophages; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Safflower Oil; Transforming Growth Factor beta

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX(-/-)) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX(-/-) mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX(-/-) mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.

Topics: Animals; Arachidonate 5-Lipoxygenase; Disease Models, Animal; Hydroxyurea; Inflammation; Intercellular Adhesion Molecule-1; Ischemia; Kidney Diseases; Leukotriene B4; Lipoxygenase Inhibitors; Mice; Mice, Knockout; Neutrophils; Peroxidase; Reperfusion Injury

Glomerular infiltration of macrophages is a characteristic alteration of renal histopathology in hyperlipidemic renal injury. Each macrophage has two key enzymes to synthesize LTB4:5-lipoxygenase and LTA4 hydrolase. In this study we examined the long-term effects of LTB4 antagonist on real function and histopathology of spontaneously hypercholesterolemic (SHC) rat, which is model of hyperlipidemic renal injury, to see if the LTB4 antagonist could reduce the progression of renal damage. Spontaneously hypercholesterolemic rats fed a normal diet (C) developed end-stage renal failure in 26 weeks, while those fed a diet supplemented with LTB4 antagonist (E) showed normal renal function, and mild histopathological alterations (SCr: C, 1.4 +/- 0.3; E, 0.6 +/- 0.1 mg/dl, P < 0.03) without statistical differences in serum total cholesterol, body weight and blood pressure between two groups. These results suggest that LTB4 plays an important role in progression of hyperlipidemic renal injury.

Topics: Animals; Blood Pressure; Body Weight; Cholesterol; Creatinine; Hyperlipidemias; Immunosuppressive Agents; Kidney; Kidney Diseases; Leukotriene B4; Male; Phenylpropionates; Proteinuria; Rats; Rats, Inbred Strains

Leukotrienes are products of the 5-lipooxygenase pathway of arachidonic acid metabolism that possess potent inflammatory properties. We examined the potential role of this pathway in the decrease in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) observed in rats after unilateral release of bilateral ureteral obstruction (BUO) of 24 hours duration. Isolated glomeruli from rats with BUO produced significantly greater amounts of leukotriene B4 (LTB4) than glomeruli from sham-operated rats (SOR; P less than 0.0001). Glomeruli from rats with BUO given MK886, an inhibitor of the 5-lipooxygenase enzyme, or from rats with BUO subjected to both total body irradiation to prevent the leukocyte infiltration of the kidney and also given MK886 prior to obstruction, produced amounts of LTB4 not significantly different from those in glomeruli of SOR. Glomeruli from rats with BUO that had only total body irradiation prior to obstruction produced significantly less LTB4 than glomeruli from untreated BUO rats, but LTB4 production was still significantly greater than in glomeruli from SOR. There were no significant differences in GFR among SOR, SOR given MK886, and SOR subjected to total body irradiation. However, SOR given MK886 had significantly higher ERPF and lower renal vascular resistance (RVR) than SOR not pretreated with the lipooxygenase inhibitor. Rats with BUO given MK886, or subjected to total body irradiation, or both, prior to obstruction had significantly greater GFR and ERPF values and lower RVR than untreated BUO rats. Glomeruli from rats with BUO which were not pretreated had three times the leukocytes of glomeruli from SOR. This leukocyte infiltrate was composed of macrophages (about 55%) and neutrophils (about 45%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonate 5-Lipoxygenase; Female; Glomerular Filtration Rate; Indoles; Kidney Diseases; Leukotriene B4; Lipoxygenase Inhibitors; Rats; Rats, Inbred Strains; Renal Circulation; Ureteral Obstruction

Macrophages, isolated from dialysis fluid of three patients with continuous ambulatory peritoneal dialysis (CAPD) at different times during peritonitis were labelled with 14C-arachidonic acid and stimulated with the calcium ionophore A23187. The main metabolites formed by 5-lipoxygenase activity were leukotriene B4 (LTB4) and 5-hydroxy-6, 9, 11, 14-eicosatetraenoic acid (5-HETE). Smaller amounts of cyclooxygenase metabolites were present and also a major compound with an elution time between 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2). This substance was isolated, analyzed by GC-MS and identified as 20-hydroxy-leukotriene B4 (20-OH-LTB4). This indicates that human peritoneal macrophages obtained from CAPD not only produce leukotrienes and prostaglandins, but also the omega-hydroxylase product of LTB4, which has been demonstrated to be present in polymorphonuclear leucocytes. The activity of this enzyme was not correlated with the severity of the peritonitis.

Topics: Aged; Chromatography, High Pressure Liquid; Fatty Acids, Unsaturated; Humans; Kidney Diseases; Leukotriene B4; Macrophages; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis