LEUKOTRIENE D(4) IS A MEDIATOR OF PROTEINURIA AND GLOMERULAR HEMODYNAMIC ABNORMALITIES IN PASSIVE HEYMANN NEPHRITIS

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous n ephropathy. 10 d after injection of anti-Fx1A antibody, urinary protei n excretion rate (Upr) in PHN was significantly higher than that of co ntrol. Micropuncture studies demonstrated reduced single nephron plasm a flow and glomerular filtration rates, increased transcapillary hydru alic pressure difference, pre- and postglomerular resistances, and dec reased ultrafiltration coefficient in PHN rats. Glomerular LTB4 genera tion from PHN rats was increased. Administration of the 5-LO activatin g protein inhibitor MK886 for 10 d markedly blunted proteinuria and no rmalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 rec eptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerul us were increased in PHN rats. In x-irradiated PHN rats, which develop ed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glo merular hemodynamic abnormalities and a hemodynamic component of the a ccompanying proteinuria. The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthas e in glomerular cells.