Murine glomerular leukotriene B4 synthesis. Manipulation by (n-6) fatty acid deprivation and cellular origin.
Leukotriene (LT) B4 is an important pro-inflammatory autocoid. In order to investigate the potential role of this eicosanoid in renal inflammation, in this study we determined the capability of glomeruli to synthesize this mediator. Glomeruli were able to synthesize LTB4 when provided with exogenous substrate in a dose-dependent fashion in the presence of ionophore A23187. Ionophore, although by itself a weak agonist for LTB4 formation, was required for LTB4 production from exogenous arachidonate. The identity of LTB4 was confirmed by specific radioimmunoassay, high pressure liquid chromatography, and gas chromatography/mass spectrometry. The synthesis of LTB4 was inhibited by BW755C (a lipoxygenase/cyclooxygenase inhibitor) but not indomethacin. Essential fatty acid (EFA) deficiency, obtained by the deprivation of (n-6) fatty acids, is known to exert a protective effect in renal inflammatory states. This dietary manipulation markedly attenuated the ability of glomeruli to synthesize LTB4. In contrast, the synthesis of cyclooxygenase products from exogenous arachidonate was increased by EFA deficiency. Because EFA deficiency has been shown to deplete glomeruli of resident mesangial macrophages, it was hypothesized that this effect accounted for the diminished LTB4 synthesis. To test this hypothesis, glomeruli were depleted of macrophages using x-irradiation. Glomeruli from these animals exhibited a marked decrease in LTB4 synthesis. Glomerular synthesis of cyclooxygenase products was unaffected by irradiation. In sum, glomeruli have the capability to synthesize LTB4, and this capacity is correlated with the presence of glomerular macrophages. EFA deficiency attenuates the ability of glomeruli to synthesize LTB4 by depleting them of macrophages.
Lefkowith
J B
JB
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110.
Morrison
A R
AR
Schreiner
G F
GF
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000172:deficiency*; D007213:Indomethacin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism*; D007975:Leukotriene B4 / Q000096:biosynthesis*; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D011917:Rats, Inbred Lew
D005227:Fatty Acids; D011720:Pyrazoles; D007975:Leukotriene B4; D000001:Calcimycin; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015232:Dinoprostone; D007213:Indomethacin