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

The role of arachidonate 12- and 5-lipoxygenation eicosanoids in mediating acute changes in renal hemodynamics was assessed in nephrotoxic serum nephritis (NSN) in the rat. Following a single intravenous injection of nephrotoxic serum (NTS), significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) occurred at one hour, and were associated with increments in glomerular polymorphonuclear leukocyte (PMN) counts and in the synthesis of thromboxane (Tx) B2, leukotriene (LT) B4 and 12-hydroxyeicosatetraenoic acid (12-HETE). Pretreatment of rats with the arachidonate 12-lipoxygenase inhibitor, baicalein, partially but significantly ameliorated the decrements in GFR and RBF, and blocked the enhanced glomerular synthesis of 12-HETE following administration of NTS. Likewise, pretreatment of rats with the arachidonate 5-lipoxygenase inhibitor, U-66858, partially ameliorated the decrements in GFR and RBF induced by NTS. Combined pretreatment of rats with baicalein and U-66858 ameliorated the decrements in GFR and RBF to an extent no different to that of U-66858 alone. In rats pretreated with the LTB4 receptor antagonist, U-75302, GFR and RBF remained depressed to levels no different than in animals which received NTS alone. These observations indicate that in NSN, the acute decrements in GFR and RBF are partially mediated by 12-HETE and arachidonate 5-lipoxygenation products. Leukotrienes other than LTB4, such as LTD4 and LTC4, are the likely candidates.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 5-Lipoxygenase; Basement Membrane; Glomerular Filtration Rate; Glomerulonephritis; Hemodynamics; Hydroxyeicosatetraenoic Acids; Kidney Glomerulus; Leukotriene B4; Male; Rats; Renal Circulation

Washed platelets were prepared from healthy children and adults, and patients with renal glomerular diseases, and incubated with [1-14C] arachidonate to measure the generation capacities of thromboxane (Tx) A2 and 12-hydroxyeicosatetraenoate (12-HETE). Tx generation capacity of platelets was significantly higher in patients with chronic glomerulonephritis, purpura nephritis and lupus nephritis than in healthy control subjects. There was no significant increase in minimal change nephrotic syndrome. 12-HETE showed a decreasing tendency in the glomerular diseases, which was restored to normal level by in vitro addition of indomethacin. Such increased Tx generation capacity of platelets may cause abnormal enhancement of platelet functions and conceivably constitute an aggravating factor of glomerular and microvascular damage in the affected kidney.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Child; Glomerulonephritis; Humans; Hydroxyeicosatetraenoic Acids; Indomethacin; Thromboxane B2

Arachidonate lipoxygenation to monohydroxylated eicosatetraenoic acids (HETE) was studied in rat nephrotoxic serum nephritis (NSN). A single infusion of nephrotoxic serum enhanced conversion of [3H]arachidonic acid ([3H]C20:4) to [3H]12-HETE in glomeruli isolated from nephritic rats compared with controls. The percent conversion of [3H]arachidonic acid was 1.95 +/- 0.2% in control glomeruli and 14.2 +/- 2% in nephritic glomeruli 2 d after induction of disease. No significant changes in the conversion of [3H]C20:4 to [3H]5-, 8-, and 9-HETE were noted. Extraction of glomerular HETE by alkaline hydrolysis, to evaluate possible reacylation of HETE after their production, confirmed the presence of 12-HETE and did not provide evidence of 5-HETE synthesis. Increased glomerular 12-HETE synthesis in nephritic rats was also demonstrated by high pressure liquid chromatography-UV detection and by 12-HETE radioimmunoassay. The enhanced glomerular 12-HETE synthesis commenced as early as 3-5 h after administration of nephrotoxic serum and peaked at day 2 with 10-fold enhancement of 12-HETE production. Increments of glomerular 12-HETE persisted on day 7 and returned toward control levels by day 14. Platelet depletion, induced by antiplatelet antisera, did not decrease glomerular 12-HETE synthesis in NSN, thereby eliminating platelets as the cellular origin of 12-HETE. Glomerular epithelial and mesangial cells are the most likely sources of enhanced 12-lipoxygenase activity. The enhanced arachidonate 12-lipoxygenation in glomerular immune injury could have important proinflammatory effects in the evolution of glomerulonephritis since 12-HETE has important effects on leukocyte function.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acids; Basement Membrane; Chromatography, High Pressure Liquid; Glomerulonephritis; Hydroxyeicosatetraenoic Acids; Kidney Glomerulus; Lipoxygenase; Male; Rats; Rats, Inbred Strains; Serum Sickness